JPH07508045A - Ornithine decarboxylase inhibitory cyclic aminooxy compounds - Google Patents

Abstract

PCT No. PCT/EP94/01035 Sec. 371 Date Dec. 12, 1994 Sec. 102(e) Date Dec. 12, 1994 PCT Filed Apr. 2, 1994 PCT Pub. No. WO94/24093 PCT Pub. Date Oct. 27, 1994.Compounds of formula (I): H2N-(CH2)n-A-(CH2)m-O-NH2 and salts thereof are described in which the radical A is C3-C6 cycloalkylene; n is 0 or 1 and, independently thereof, m is 0 or 1; with the provisos that a) the distance between the aminooxy radical H2N-O- and the amino group -NH2 is at least 3 and not more than 4 carbon atoms and that b) the two radicals H2N-(CH2)n- and -(CH2)m-O-NH2 are not bonded to the same ring carbon of A. The compounds of formula (I) and their salts are ornithine decarboxylase inhibitors.

Description

[Detailed description of the invention] Ornithine decarboxylase inhibitory cyclic aminooxy compounds The present invention provides novel Pharmacologically Active Aminooxy Compounds, Processes for Producing Darkening Compounds, and Such Compounds A pharmacological preparation, prophylactic, therapeutic or for the treatment of the human or animal body, comprising Diagnostic methods and for prophylactic or therapeutic treatment of the human or animal body and pharmacology Concerning the use of such compounds for the manufacture of pharmaceutical preparations.

Polyamine spermidine in the regulation of growth processes according to the current state of knowledge (polyamines spermidine) and spermine (sper+ 5ine) and diamine putrescine Participation in e) is estimated.

Cellular functions of polyamines can be favorably influenced by inhibition of polyamine biosynthesis. Ru.

The enzyme ornithine decarboxylase (ODC) is an important enzyme in polyamine biosynthesis. one of. Reduced activity of ODC leads to reduced polyamine biosynthesis and therefore leading to a decrease in polyamine levels in cells.

If inhibition of the activity of this enzyme by ODC inhibitors could be achieved in mammals Polyamine concentrations in cells (including human cells) are influenced by It is lowered with the help of ODC inhibitors.

In mammalian cells, ODC is putrescine, i.e. at the same time the polyamine It catalyzes the synthesis of diamines, which are also intermediates in biosynthesis.

Surprisingly, it has now been found that the compounds of the present invention having a cyclic central component have advantageous pharmacological properties. It was discovered that it has many scientific properties.

The compound according to the present invention has the following formula (1): H, N-(CH, ), -A-(C H! '), -0-NH! (1) (in the formula, the A group is C=-Cs cycloalkylene; n is 0 or l, and each other independently, the theory is 0 or l; However, a) the distance between the aminooxy group H, N-0- and the amino group -NHl is small. at least 3 and 4 carbon atoms, most preferably b) two groups HtN-(CHt )-- and -(CH!), -0-NH, are bonded to the same ring carbon atom of ^ not present. ) and their salts.

The compounds according to the invention may be present as a mixture of cis and trans isomers or preferably as a mixture of cis and trans isomers. can exist as pure cis or trans isomers; asymmetric carbon atoms If present (i.e. A is 1,4-cyclohexylene or 1,3-cyclobutylene) In cases other than tyrene), these carbon atoms are independently (R), (S) or (R,S') configuration. mixture of cis and trans isomers In each case, both the optical and transisomers of the cis and trans isomers or only one of them can be present. pure cis or trans isomer as a pure enantiomer or as a mixture of enantiomers, e.g. that can exist as semi-mixtures, especially as pure enantiomers is preferred.

The terms and general expressions used in the description of the invention are preferably defined as follows: Define: Two groups H2N-(CI, ), - and -(C8t), -0-NH, C, -C, cycloalkylene A that is not bonded to the same ring carbon atom is a cyclic hydrocarbon and 1,2-cyclopropylene; l, 2- or 1°3- Cyclobutylene; l, 2- or! , 3-cyclopentylene; and 1.2-, 1. selected from 3- or 1,4-cyclohexylene; l,2-cyclopropylene; 1 ゜3-cyclobutylene, 1,3-cyclopentylene or 1.3- or 1. 4-cyclohexylene is preferred.

Aminooxy groups H of at least 3 and up to 4 carbon atoms, N-0- and amino groups- The distance between the group H2N-(CHt ) would include the shortest linkage between R- and the group -(CH*)--0-NH* It is defined as follows. The numerical values of n and ■ are chosen according to the context of condition a); Preferably n is 0 and pus is 0 or l.

The salts of the compounds according to the present invention are acid addition salts, particularly pharmacologically acceptable acid addition salts, That is, acid addition salts that do not have significant toxicity at the particular doses to be used, e.g. with organic salts, such as hydrochloric acid, sulfuric acid or phosphoric acid, or with suitable organic carboxylic acids or is a sulfonic acid, such as acetic acid, octanoic acid, succinic acid, adipic acid, fumaric acid, Hydroxymaleic acid, propionic acid, lactic acid, malic acid, citric acid, salicylic acid , p-aminosalicylic acid, ascorbic acid, oxalic acid, benzenesulfonic acid, 1 ．． 5-naphthalenedisulfonic acid, methanesulfonic acid or 1,2-ethanedis with sulfonic acid, with N-cyclohexylsulfamic acid, or with e.g. amino acids, For example, salts with glutamic acid or aspartic acid. - or the binary exists may be formed depending on the basicity of the basic group being used.

Pharmacologically unsuitable salts, such as picrate or percolate, can be isolated or purified. It can be used for Only pharmacologically acceptable salts are used therapeutically and therefore suitable.

The compounds according to the invention have properties that are particularly useful in pharmacological applications.

Surprisingly, the compound of formula (+) is particularly effective for diamine oxidase (DAO). Effective against the enzyme ornithine decarboxylase (ODC), which is specific for It was recognized that the drug had a specific inhibitory effect.

These are new classes of ODC inhibitors.

ODC is a polyamine that occurs in all cells of mammals including humans. It plays an important role as a key enzyme in biosynthesis. Poly in cells Amine concentration is controlled by ODC. Inhibition of the enzyme ODC depends on the concentration of polyamines. bring about a decline. Because a decrease in the concentration of polyamines causes inhibition of cell proliferation, By administering ODC inhibitors, eukaryotic and even prokaryotic cells, especially rapidly It suppresses the growth of cells that grow in a controlled manner or in an unregulated manner, and even kills cells. It is possible to suppress the onset of cell division.

Inhibition of the enzyme ODC can be achieved by, for example, J, E, 5eely and A, E, Pegg 0 rnithineDecarboxylase (Mouse Kidney) , pp. 158-161. H, Tabor and C.

White-Tabor (ed.): Methods in Enzymdog y, Volume 94: Polya IInes.

By the method of ^cadeIIlic Press, New York, 1983. can be demonstrated. ODC derived from rat liver was used in this test (isolation). : Hayashi, S.-1, and Kameji, T., same volume, p. 154- 158), about 0.018 M for the compound of formula (1), preferably about 0. O1-10 μM, e.g. down to about 0.02 to about 7.2 μM micromolar ICs in the area. value is obtained. I.C. , the ODC activity is free from the inhibitor. The concentration of inhibitor is 50% of the control.

As ODC inhibitors, the compounds of formula (1) have antiproliferative properties, which can be seen in e.g. This was proven by demonstrating an inhibitory effect on the proliferation of human T24 bladder cancer cells. child demonstrated that such cells were treated with ``Eagle's Best'' supplemented with 5% (V/V) fetal bovine serum. in a humid incubator at 37°C and 5% CO7 by volume. This is done by an incubation procedure in air. This cancer cell (100 0-1500) into a 96-well microtiter plate and Incubate overnight under conditions. The test substance is added in serial dilutions on day 1. . The plate is incubated under the above conditions for 5 days. During this period, Troll cultures undergo at least four cell divisions.

After incubation, these cells were treated with 3.3% (weight/volume = W/V) aqueous Fixed with glutaraldehyde solution, washed with water, rinsed with O,OS% (w/v) water stain with methylene blue solution. After washing, the dye was dissolved in 3% (w/v) aqueous salt. Elute with acid salt. Then, the optical density (OD) per hole is directly proportional to the number of cells. Measured at 665 nm using a thermometer (Titertek multiskin) . The IC. The value is calculated by a computer system using the following formula:

The IC6° value is determined by the number of cells per drop at the end of the incubation period. It is defined as the concentration of active ingredient when there are only 50% of the number of cells in the culture. formula (IC of compounds of D, values preferably range from 10 to 2.5 XlO'M .

Compounds of formula (1) therefore inhibit diseases that respond to inhibition of ornithine decarboxylase. It is particularly suitable for the treatment of diseased conditions such as benign and malignant tumors. these are tumors can cause degeneration and even increase tumor cell metastasis and micrometastases. It can prevent breeding. They are also associated with protozoal infections such as trypanosomiasis, Laria, or Pneumolystis carinii (PneuIIlonocysti) It can be used to treat pneumonia caused by S. carinii).

Compounds of formula (1) can be quite well tolerated. This was confirmed by tests on rats. Can be evidenced by: Healthy male albino rats (Tif: RAI) weighing 130-250 g F (SPF), CIBA Animal Production, 5tein, Switzerland) has a pelletized standard food (NAFAG No. 890; NAFAG, Gossau, 5w1tzerland) and water as needed. . Compound of formula (+) in aqueous lon+ 20.60 or 200 mg/k g (concentrations 0, 2, 0.6; and 2.0%) by separate artificial feeding for 14 days. Rats are given daily boosts over a period of time. For example, the following data may be used during the administration period. Find out: mortality, clinical signs, body weight, food consumption, water consumption, hearing, clinical biochemistry , hematology, urine analysis, autopsy. Results: 200 mg of the investigated compound of formula (1) daily Doses up to /kg were tolerated without significant signs of toxicity.

Compounds of formula (1) can be used as selective ODC inhibitors or in combination with other pharmacologically active substances. Can be used as a combination.

Possible combinations include, for example: (a) inhibitors of other enzymes of polyamine biosynthesis; , for example, S-adenosylmethionine decarboxylase inhibitor, (b) tan inhibitor of protein kinase C, (C) inhibitor of tyrosine protein kinase, ( d) cytokines, (e) negative growth regulators, (') aromatase (arrow+a (g) antioestrogens ) or (h) contains a conventional cytostatic active ingredient.

Preferred compounds of formula (+) are: During the ceremony, A group is C, -C, cycloalkylene; n is 0 or l, and each other independently, m is 0 or l; However, a) the distance between the aminooxy group HI N-0- and the amino group -NH is small. at least 3 and up to 4 carbon atoms, and b) two groups Hffi N-( CH! ), - and - (CH!), -0-NH, to the same ring carbon atom of A If unbonded and asymmetric carbon atoms are present, cis and trans isomers As a mixture, preferably the cis or trans form, especially the pure enantiomers as; (if asymmetric carbon atoms are present, as an enantiomeric mixture or , especially as the pure enantiomers), especially as present in the trans form compounds; and salts thereof.

Particularly preferred compounds of formula (1) are: During the ceremony, the A group is C5-Cs cycloalkylene; n is 0; and m is 0 or l; However, a) the distance between the aminooxy group H, N-0- and the amino group -NH is small; at least 3 and 4 carbon atoms, most preferably b) two groups 82N-(CH2 )-- and -(C)+1)-0-NHt are bonded to the same ring carbon atom of ^ and if an asymmetric carbon atom is present, in the cis and trans forms or As a mixture of cis or trans forms, preferably in cis or trans form. especially as pure enantiomers; (if asymmetric carbon atoms are present, (as an enantiomeric mixture or especially as a pure enantiomer) and their salts.

More particularly preferred compounds of formula (1) are: A group is Cs-Cs cycloalkylene; n is 0, and Cabinet is 0; However, a) the distance between the aminooxy group H, N-0- and the amino group -NH is small; at most 3 and 4 carbon atoms, and b) two groups HtN-(CHt ) -- and --(CH*), -0-NH* are bonded to the same ring carbon atom of A and if an asymmetric carbon atom is present, in the cis and trans forms or As a mixture of cis or trans forms, preferably in cis or trans form. especially as pure enantiomers; (if asymmetric carbon atoms are present, (as an enantiomeric mixture or especially as a pure enantiomer) and their salts.

Very particularly preferred compounds of formula (1) are A group is 1,2-cyclopropylene; l,3-cyclobutylene; 1,3-cyclope or 1,3- or 1,4-cyclohexylene; m is 0 or l, and n is 0 or l independently of m; However, if the distance between the aminooxy group 82 N-0- and the amino group -NH is small, Both have 3 and 4 or less carbon atoms; when asymmetric carbon atoms are present, cis and preferably in the trans and trans forms or as a mixture of the cis or trans forms. , in cis or trans form, especially as a pure enantiomer: (asymmetric carbon If elementary atoms are present, they can be used as enantiomeric mixtures or especially as pure enantiomers. such compounds as present in particular in the trans form (as trans siomer); and It is the salt of

Particularly preferred compounds of formula (1) are: During the ceremony, A group is 1,2-cyclopropylene; 1,3-cyclobutylene; or 1,3- or 1,4-cyclohexylene; m is O or l, and n is 0 or l independently of l; However, a) the distance between the aminooxy group H, N-0- and the amino group -NH is small; at least 3 and 4 carbon atoms, b) A is 1,2-cyclopropylene or In the case of 1,3-cyclobutylene, n is 0 or l; an asymmetric carbon atom is present. in cis and trans forms or a mixture of cis and trans forms, if present. as compounds, preferably in cis or trans form, especially in pure enantiomers. as an omer; (if an asymmetric carbon atom is present, as an enantiomeric mixture) or especially as pure enantiomers), particularly in trans form and their salts.

Particularly preferred compounds of formula (1) are: During the ceremony, A group is 1,2-cyclopropylene; 1,3-cyclobutylene; l,3-cyclope ntylene: or 1,3- or 1,4-cyclohexylene; n is 0; ri, and ■ is 0 or l; However, the distance between the aminooxy group HI N-0- and the amino group -NH snow is small. Both have 3 and 4 or less carbon atoms; when asymmetric carbon atoms are present, cis and preferably in the trans and trans forms or as a mixture of the cis or trans forms. , in cis or trans form, especially as a pure enantiomer; (asymmetric carbon If elementary atoms are present, they can be used as enantiomeric mixtures or especially as pure enantiomers. such compounds as present in particular in the trans form (as trans siomer); and It is the salt of

Highly preferred compounds of formula (1) are: During the ceremony, the A group is 1,4-cyclohexylene, n is 0, and ■ is 0, and as present in cis or trans form, especially in trans form. compounds; and their salts.

Highly preferred compounds of formula (1) are: During the ceremony, the A group is 1,3-cyclobutylene, n is 0, and ■ is 0 or l (particularly l is 1), and is in the cis or trans form. and especially those compounds which exist in trans form; and salts thereof.

Finally, highly preferred compounds of formula (1) are the A group is 1,2-cyclopropylene, n is 0 or 1, and m is 1, may exist in cis or trans form, especially in trans form. compounds; and their salts.

In particular, the compounds of formula (1) and their salts described in the Examples, especially as pharmaceuticals. salts that are acceptable over all others are preferred over all others.

The novel compounds of formula (1) and their salts can be prepared by methods known per se, for example, Formula (II) below: X, X2 N-(CH2), -A-(CHt), -0-NX I X, (11) in formula 1, A, n and theory are the same as defined for the compound of formula (1), with the proviso that 1) -0-NX　*　The distance between 4 groups of X and X, X, N- groups is at least 3 and 4 The following carbon atoms, and 1i) 2-horned group X+XtN-(CHy) -- and -(C)I　l　), -0-NX　I　X　1 is bonded to the same ring carbon atom of A have not done so, and L, Xt, Xs and x4 are each independently hydrogen or a -valent amino protecting group , X, and Xs, Xs and X, or X, and Xt, and X.

and x4 in each case can also be taken together to form a divalent protecting group; other functional groups which do not participate in the reaction are optionally present in protected form; However, base X...X! , at least one of Xs and x4 is an amino protecting group ) or their salts, or if a salt-forming group is present, the amino reserve of the present Separate the guardian group, and, if desired, converting the compound of formula (1) obtainable into another compound of formula (1). separation of the obtainable isomer mixture into individual isomers, and/or The free compound of formula (1) that can be converted into a salt or the compound of formula (1) that can be obtained A salt of a compound may be prepared by a procedure that converts the compound into the free compound or another salt.

Detailed description of preferred mutagenesis methods Unless otherwise specified, the groups A in the starting materials and in the final products below, rn and n are as defined for the compound of formula (1).

The conditions for compounds of formula (+) should also apply accordingly.

Removal of protecting groups: Protecting groups for functional groups, especially amino and hydroxyl groups, in the starting materials include , in particular customary protecting groups, such as peptide compounds, cephalosporins, Includes those commonly used in the synthesis of penicillins, nucleic acid derivatives and sugars. It will be done. These protecting groups may already be present in the intermediate and Functional groups should be protected from undesired side reactions. The characteristics of the protecting group are: It can be easily introduced and separated without any side reactions. It also lies in the fact that it is not in the final product. Protecting groups and their removal are well known. and, for example, Protecting groups and their emoval are known per se and are desc Ribed, for exaw+ple.

in J, F, W, McOmie, Protective Groups "in Organic Chemistry".

Plenum Press, London, New York, 1973 and T., W., Greene, “ProteC-tive Groups i n Organic 5ynthesis”, Wiley, New Yor K., 1984. Amino protecting groups can be monovalent or divalent. Wear.

Suitable monovalent amino protecting groups X, , X, , Xs and x4 are acyl groups, preferably is lower alkanoyl, such as formyl, acetyl or propionyl, halo lower Alkanoyl, such as 2-halogenoacetyl, especially 2-chloro-12-bromo- 12-iodo-, 2,2,2-trifluoro- or 2゜2.2-trichloroacetic acid methyl, benzoyl and unsubstituted or e.g. halogen, lower alkoxy , substituted by lower alkoxycarbonyl or nitro, e.g. Benzoyl, 4-chlorobenzoyl, 4-methoxybenzoyl, 2-methoxybenzoyl Rubonyl-benzoyl or 4-nitrobenzoyl, acyl of carbonic acid half ester groups, especially arylmethoxycarbonyl containing one or two aryl groups (those is preferably phenyl, naphthyl or 9-fluorenyl, unsubstituted or or for example lower alkyl, especially tert-lower alkyl, such as tert-butyl lower alkoxy, such as methoxy, hydroxyl, halogen, such as bases and and/or nitro), e.g. unsubstituted substituted or substituted benzyloxycarbonyl, e.g. 4-nitrobenzyloxycarbonyl carbonyl, or substituted diphenylmethoxycarbonyl, such as di(4-methoxycarbonyl) phenyl)-methoxycarbonyl, 2-halo lower alkoxycarbonyl, e.g. B2.2.2-Trichloroethoxycarbonyl, 2-bromomethoxycarbonyl or 2-iodoethoxycarbonyl, lower alkoxycarbonyl, especially lower Rukoxycarbonyl branched at the 1st position of the lower alkyl group or substituted in the 1- or 2-position, especially tert-lower alkyl Koxycarbonyl, such as tert-butoxycarbonyl, or primary lower alkoxycarbonyl oxycarbonyl, e.g. ethoxycarbonyl, alkylformimidoyl, e.g. lower alkyl-formimidoyl, e.g. , sulfo(-3O,l+) (which is in salt form, e.g. alkali metal or ammonium salts (which may be present in the form of sodium or potassium salts), or arylmethyl groups, such as mono-, di- or especially triarylmethyl (the arylmethyl group In particular, phenyl groups may be unsubstituted or substituted, such as benzyl, diphenyl groups, etc. nylmethyl or triphenylmethyl (trityl)).

Particularly preferred monovalent amino-protecting groups Xl+L, Xs and x4 are carbonate half esters acyl groups, especially lower alkoxycarbonyl, such as tert-butoxycarbonyl unsubstituted carbonyl or ethoxycarbonyl, benzyloxycarbonyl or substituted, e.g. as described above, e.g. 4-nitropene Zyloxycarbonyl, diphenylmethoxycarbonyl or 2-halo lower alkyl Koxycarbonyl, e.g. 2.2.2-trichloroethoxycarbonyl; trithi lower alkanoyl, such as formyl and acetyl, 2-methoxycarbonyl - a benzoyl or lower alkylformimidoyl group, especially when the lower alkyl group is Those who have won once or twice in first place, such as tert-butyl- It is formimidoyl. Among the above, preferred protecting group Xl or x2 is lower alkyl xylcarbonyl, such as tert-butoxycarbonyl or lower alkanoyl , for example acetyl.

Preferred two groups consisting of groups x1 and X7 and/or Xl and/or X The amino protecting group is a mono- or di-substituted methylidene group (X, and oxime derivatives), such as 1-lower alkoxy (particularly methoxy or ethoxy) xy)-lower alkylidene (e.g. -ethylidene or -1-n-butylidene), For example =C(C)Is)(OCtHi), l-lower alkyl (particularly methyl or ethyl)-lower alkylidene (especially -1-ethylidene), such as C(CL)-1 or l-phenyl-lower alkylidene, such as =CH-phenyl, and hydrocarbons A dicarboxylic acid group, preferably linked to the nitrogen to be protected via both carbonyl groups. combinations (resulting in bisacyl derivatives), especially phthaloyl or hydrogenated species Analogs as above for unsubstituted or substituted benzoyl substituted with the same substituent as, for example, a phthaloyl group (this is a IH-isoindole-1,3(2H) dione group (F) together with the nitrogen atom to be protected. forming a thalimide group) or the corresponding dihydro-, tetrahydro- or xahydro-phthaloyl group, lower alkyl-dicarboxylic acid group, e.g. succinic acid group , a lower alkenyldicarboxylic acid group, such as a maleic acid group, or a CS-+t-bisic acid group. The dicarboxylic acid group is, for example, a 5-norbornene-2,3-dicarboxylic acid group.

The protecting group can be removed in the process according to the invention in a manner known per se, for example by solvolysis, in particular by hydrolysis, alcoholysis, aminolysis, hydrazinolysis or acidolysis. by reduction, especially by hydrogenolysis, by photolysis or with the aid of enzymatic methods. Can be separated. Simultaneous or stepwise elimination of all of the protecting groups present will ensure that no protecting groups are removed. It is possible to further use the partially removed intermediate in unpurified or purified form. .

Elimination of protecting groups is described, for example, in the standard articles mentioned above.

The amino-protecting group or groups may be protected stepwise or simultaneously depending on the type of protecting group. in a known manner, for example by reduction or solvolysis, particularly preferably in an acidic medium. Hydrolysis results in alcoholysis, acidolysis, aminolysis or hydrazinolysis. separated by the solution.

lower alkoxycarbonyl, such as a tert-butyloxycarbonyl group, or A trityl group can be used, for example, with acids, such as mineral acids, such as sulfuric acid or hydrohalic acids, such as solvents, especially alcohols, such as methanol or ethanol, for example with hydrochloric acid, or ethers, such as tetrahydrofuran or diethyl ether, or organic water or in the presence or absence of an acid such as formic acid, acetic acid or trifluoroacetic acid. -20°C to reflux temperature in the presence or absence of an organic solvent such as methylene chloride may be liberated by treatment at a suitable temperature, in particular θ°C to room temperature, or at reflux temperature. . Primary lower alkoxycarbonyl is preferably used under alkaline conditions, e.g. bases such as alkali metal hydroxides such as sodium hydroxide or potassium hydroxide. water, aqueous solvents such as alcohol/water mixtures, such as ethanol /water or methanol/water, or alcohols such as methanol or ethanol at a suitable temperature specified for acid cleavage of lower alkoxycarbonyl. and release it. Unsubstituted or substituted benzyloxycarbonyl groups can be hydrogenolyzed, for example. by treatment reductively, i.e. with hydrogen in the presence of a suitable catalyst, e.g. palladium. or by sodium in liquid ammonia, or by acidolysis, Particularly cleavable with hydrogen bromide/glacial acetic acid. 2-halo lower alkoxycarbonyl for example with a suitable reducing agent such as zinc, an organic solvent such as methanol or water. can be separated by treatment in the presence of acetic acid. Lower alkyl-formy Midoyl, e.g. tert-butylformimidoyl, is preferably a base, e.g. Can be cleaved by hydroxides, especially alkali metal hydroxides, e.g. potassium hydroxide . Hydrocarbon dicarboxylic acid groups, especially phthaloyl groups, can be removed by e.g. hydrazinolysis. , for example further water (which can also be added initially during the reaction) and/or organic solvent, such as an alcohol, such as ethanol, or an ether, such as diethyl A suitable temperature between 0° C. and reflux temperature, e.g. 20° C., in the presence or absence of ether. Aminolysis by hydrazinolysis with hydrazine hydrate at ~30°C or reflux temperature By decomposition, e.g. primary amines, e.g. lower alkyl amines, e.g. amines, cycloalkylamines such as cyclohexylamine, or arylamines aniline, or ammonium salts, preferably polar solvents, e.g. Alcohols such as methanol or ethanol, liquid chlorinated hydrocarbons such as salts in the presence or absence of methylene chloride or chloroform, or (if ammonium hydroxide (if U is used as a base) in water at a suitable temperature between 50° C. and reflux temperature, especially by aminolysis at reflux temperature or by acids, especially mineral acids such as sulfuric acid or halo Hydrogenic acid, e.g. hydrochloric acid, in water, organic solvents, e.g. alcohols, e.g. For example, in the presence or absence of methanol, from 50°C to reflux temperature, especially at reflux temperature. Can be separated by acid. Unsubstituted or substituted benzoyl is preferably alkali or is under acidic conditions, e.g. hydroxide bases, e.g. alkali metal hydroxides, e.g. With sodium hydroxide or potassium hydroxide, water or an aqueous solvent, e.g. in a coal mixture, e.g. water/ethanol or water/methanol, from 50°C to at a suitable temperature of the boiling point of the reaction mixture, especially at reflux temperature, or with sulfuric acid or halogenated water. water or an aqueous solvent, such as a water/alcohol mixture, in the presence of a basic acid, such as hydrochloric acid; e.g. in water/methanol or water/ethanol in the presence of a hydroxide base. Detach at a suitable temperature as mentioned for detachment. Due to release of lower alkanoyl protecting group may include, for example, hydroxy bases, such as alkali metal hydroxides, such as sodium hydroxide. 50°C to reflux temperature in water or aqueous solution with potassium or potassium hydroxide alkaline hydrolysis at a suitable temperature, e.g. at reflux temperature or, e.g., mineral acids, heating, e.g. with hydrohalic acid or sulfuric acid, e.g. with aqueous hydrochloric acid or sulfuric acid. Acid hydrolysis under the influence of, for example at the temperatures mentioned above, is preferably used. vinegar Rufo (including salt forms) is preferably a sulfuric or hydrohalic acid, e.g. With an acid in water or an aqueous solvent at a suitable temperature from 50°C to reflux temperature, e.g. In the context of team distillation, it is preferable to remove by detachment under acidic conditions. stomach. The l-lower alkyl-lower alkylidene is preferably prepared under acidic conditions, e.g. in the presence of an acid or a hydrohalic acid, e.g. hydrochloric acid, in water or an aqueous solvent at 50°C. - cut at a suitable temperature of the boiling point of the reaction mixture, e.g. under reflux or steam distillation. Let go. The l-lower alkoxy lower alkylidene is preferably an acid, such as sulfuric acid or In the presence of a hydrohalic acid, e.g. hydrochloric acid, an organic solvent, e.g. an ether, e.g. in diethyl ether, in the presence of water, at a suitable temperature between 0 and 50°C, especially at room temperature. It is released by reaction with

Phenyl-lower alkyl-methyl, e.g. 1(S)-phenylethyl, is hydrogenated By decomposition, e.g. noble metal catalysts, e.g. support materials e.g. Luminium, silica gel, barium sulfate, strontium sulfate, calcium carbonate Hydrogen in the presence of alcohols, e.g. Lucane hydroxide, e.g. in ethanol from 0°C to reflux temperature, e.g. For example, it can be decomposed at about 50°C, preferably under normal pressure.

The starting material of formula (11) is prepared by methods known per se, for example by Houben- Weyl, Methoden der Organischen Chemie (Methods of OrganicCheInistry), Volui +e X/1 (1971) and Volume E 16a (1990) It can be synthesized by a method similar to that described in .

The compound of formula (I+) preferably has the following formula (III): (C1l, ), -A- (CIl, ), -w+ (Ill) In the formula 1, ^, n and 1 are the same as defined for the compound of formula (a)- The distance between the W, group and the X, XtN- group is at least 3 and not more than 4 carbon atoms; b) Two groups -(CIl t)--W+ and X+XrN- (CHt　)-- is not bonded to the same ring carbon atom of ^; and X, and X are independently hydrogen or a -valent amino protecting group, provided that At least l of the t groups is an amino protecting group, or X+ and x2 together can also form a divalent protecting group, and Wl is a hydroxyl or a leaving group. Starting materials represented by 1 or their From salt; The following formula (m: X I X, N-011 (IV) (In the formula, X, and X are as defined for compounds of formula (th). by 1 It is synthesized by reaction with the represented hydroxyamines or their acid addition salts.

In compounds of formula (Ill), the group W1 is a hydroxyl or a leaving group, preferably is a derivatized hydroxyl group, e.g. substituted with an aliphatic or aromatic substituent. Sulfonyloxy, e.g. lower alkanesulfonyloxy, e.g. methanesulfonyloxy Nyloxy, or arylsulfonyloxy (=aryl-sow-o-) ( Aryl here has 6 to 14 carbon atoms, preferably phenyl, naphthyl , indenyl or indanyl and is unsubstituted or up to 3 groups, For example, lower alkyl, such as methyl, lower alkoxy, such as methoxy, or fluorine, chlorine or bromine), e.g. Kylphenylsulfonyloxy (=lower alkylphenyl-3Q, -0-), e.g. For example p-toluenesulfonyloxy, substituted lower alkanesulfonyl groups, e.g. Halo lower alkanesulfonyl, such as trifluoromethanesulfonyl, or is a free hydroxyl group or a halogen atom, such as chlorine, bromine or iodine. Ru.

If Wl is hydroxyl, this is a preferred process for the preparation of compounds of formula (II). (a suitable embodiment), the reaction is preferably carried out by an intramolecular dehydration reaction. Special An appropriate reaction is a variant of the Mitsunobu reaction (Synthesis , 682 (1976)), in which a compound of formula (II) is Amino-protected hydroxylamine of the formula (m) whose amino group is preferably (protected by any divalent amino protecting group), e.g. N-hydroxy Phthalimide, N-hydroxy-5-norbornene-2,3-dicarboxylic acid imide or acetohydroxamic acid ethyl ester, especially N-hydroxyphthalimide and and triarylphosphines, the aryl preferably having 6 to 14 carbon atoms. -ring, bicyclic or tricyclic, such as phenyl, naphthyl, indenyl or is indanyl), e.g. triphenylphosphine, and N,N'-a zodicarboxylic acid diester, such as N,N'-azodicarboxylic acid diester, For example, N,N'-azodicarboxylic acid di-lower alkyl ester, such as diethyl N,N'-azodicarboxylate and preferably an aprotic solvent, e.g. Ethers, such as cyclic ethers, such as tetrahydrofuran, or especially aromatic solvents. in a medium such as benzene, toluene or xylene, with the removal of an inert gas, or under an active gas, such as nitrogen or argon, and at a suitable temperature between 0°C and 80°C. The reaction is carried out at a temperature of 10 DEG to 40 DEG C., for example 20 DEG to 30 DEG C. The reaction is favorable is carried out such that the inversion occurs on the carbon atom bearing the hydroxyl group.

This reaction is carried out using divalent amino protecting groups, especially both compounds in the resulting compound of formula (11). Protected by a hydrocarbon dicarboxylic acid attached through a carbonyl group yields an aminooxy group.

HydroxyWl is an N-carbonic acid lower alkyl ester and, for example, ethyl ethyl carbonate. Ster-acid (H,C,-0-(C=0)-Nl) in an organic solvent, e.g. Bonic acid amides, e.g. dimethylformamide, or ethers, e.g. 20° C. to reflux temperature, preferably in a diethyl ether, such as diethyl ether. lower alkoxycarbonyl by nitrene insertion by reaction at reflux temperature. It can also be converted to aminoxy.

If Wl is a derivatized hydroxyl as described above, especially a halogen atom, e.g. or arylsulfonyl, such as toluenesulfonyl, the reaction is preferably an amino-protected hydroxylamine of formula (m) (In that case, X and x4 together represent a carbonyl group or a mono- or di- - Hydrocarbon dicarboxylic acid groups bonded via substituted methylidene groups, especially mono to lower Alkyl-alkylidene or 1-lower alkoxy-lower alkylidene; do X3 is sulfo, and X is sulfo, or One of x3 and Alkoxycarbonyl, benzyloxycarbonyl, 2-halo lower alkoxy carbonyl, lower alkyl-formimidoyl, unsubstituted or substituted benzoy alkanoyl, lower alkanoyl or sulfo). In this case, the formula (III The reaction of a compound of formula (m) with a compound of formula (m) is preferably carried out in an organic solvent, such as an aromatic Alcohols, such as low polar solvents such as di-alkanols such as methanol or ethanol. -Lower alkyl-carboxylic acid amides, such as dimethylformamide, rukylsulfoxides, e.g. dimethylsulfoxide, nitriles, e.g. acetonyl lyl, ketones, such as di-lower alkyl ketones, such as acetone, or ethers , e.g. cyclic 1-methyl, e.g. tetrahydrofuran or dioxane, water (as required) detergents, such as Zephird™ (=benzoylidene Contains other alkyl groups instead of thyl-ammonium chloride and dodecyl Its analogue; Bayer, Federal Republic of Ge rw+any)) or in a mixture of the above solvents, the reaction is preferably under anhydrous conditions or In the absence of an aprotic solvent, a basic reagent or catalyst, especially a base, such as a carbonate or is a bicarbonate, e.g. an alkali metal carbonate, e.g. carbonic acid or potassium bicarbonate. or sodium carbonate or bicarbonate (if necessary, crown ethers, e.g. (in the presence of dibenzo-18-crown-6), alkali metal hydrides, e.g. Sodium hydride, alkali metal amide, e.g. sodium amide, alkali gold Genus alcoholades, such as sodium methoxide or sodium ethoxide ( This can be prepared in situ by the addition of alkali metals to the alcohol in question. ), sterically hindered amines such as tertiary amines such as triethylamine, N, N, N', N'-tetramethyl-methylenediamine or 1,8-di Azabicyclo[5,4,0]undec-7-ene (1,5-5), hydroxy alkaline metal hydroxides, such as sodium hydroxide or potassium hydroxide. The salt of the compound of formula (1v) directly in the absence or presence of um, or on a salt substrate. or by preparing them in situ (e.g. alkaline (by addition of metals, e.g. sodium or potassium) at temperatures between 0°C and reflux. at a suitable temperature or with evaporation, especially at 20°C and 40-80°C, At reflux temperature or with evaporation, an inert gas such as argon or It is carried out with nitrogen, and the skilled person is able to choose particularly suitable conditions.

A preferred method for the synthesis of compounds of formula (1) is the synthesis of formulas (III) and (1v). reaction of a compound, protected as defined in the method for the reaction steps below. Subsequent removal of the group provides the compound of formula (11).

Compounds of formula (III) and (1v) are known, commercially obtainable or These can be synthesized by methods known per se.

Compounds of formula (III) are for example! Iouben-Wey1.　Mejhoden Der OrganischcnChemie (Methods of Organic Chemistry) Volume XI (1971) and volume E16a (1990). sell. In particular, they are prepared as follows: The following formula (V): tit N-(CH2), -A-(C112), -W, "(V)( During the ceremony, Wll is hydroxyl, ^, n and m are the same as defined for compounds of formula (+), with the proviso that a )-W, ° group]1. carbon atoms with a distance of at least 3 and not more than 4 to the N- group and b) two groups -(CHt), -Wl" and H2N-(CH2 ). - is not bonded to the same ring carbon atom of A (these compounds have the formula (II I), W is hydroxyl, xl and X are replaced by hydrogen atoms, and such that the remaining groups are the same as defined for compounds of formula (III). matches the compound. ). ), Wl is hydroxyl. The introduction of a protecting group into the compound of formula (III) in the synthesis of the compound of formula (Iv) during the standard operations described above or under conditions such as those described below. is converted by a reaction with a reagent that introduces protecting groups xl and/or xt (i or 3° and x4 or CX4' (7) Instead, X, and X.

is used here in the starting compound. ).

For example, the acyl groups X+ and X, for amino group acyl compounds and for protecting group It is introduced by the customary method for introduction.

A particularly preferred preparation is a compound of formula (III) where One of the groups x1 and X is hydrogen, and the other is an acyl group of the carbonic acid half ester. groups, especially lower alkoxycarbonyl, such as tert-butoxycarbonyl or benzyloxycarbonyl, and the other groups are as defined) , an activated acid derivative of formula (Vl) Qlt (Vl) from a compound of formula (V) (In the formula, Q is an acyl group of carbonic acid half ester, especially lower alkoxycarbonyl or benzyl group. oxycarbonyl, while W2 is a reactive derivatized hydroxyl group, preferably a zolides, such as imidazolides, halogens, such as chlorine or bromine, or especially acyl A group that is bonded to Q through the same carbonic acid half ester oxa (Thus, the compound of formula (■1) is a symmetric acid anhydride, that is, a diester of a dicarbonate. This is due to the reaction of )). The activated acid derivative of formula (■1) is in situ For example, carbodiimides, such as N, N'-dilower alkyl- or N, N' -C, -C, cycloalkylcarbodiimide, e.g. diisopropylcarbodiimide In the presence of diimide or N,N'-dicyclohexylcarbodiimide, In some cases activated catalysts such as N-hydroxysuccinimide or N-hydroxyben Zotriazole that is unsubstituted or substituted with halogen, lower alkyl or lower It can also be prepared by reaction in the presence of a substituted alkoxy. good Conveniently and suitably salts such as alkali metal halides such as sodium chloride are used. can be added.

The reaction is preferably carried out in an inert solvent, such as an ether, such as a fatty ether, For example diethyl ether, or cyclic ethers such as tetrahydrofuran or diethyl ether. oxane, liquid chlorinated hydrocarbons such as methylene chloride or chloroform, or N , N-dilower alkyl-lower alkanecarboxylic acid amides, e.g. dimethylform amides, or mixtures thereof (especially cyclic ethers or N,N-di-lower aryl) If alkyl-lower alkanecarboxylic acid amide is used, water may also be present. (possible); O<0>C to reflux temperature, preferably 15 to 35<0>C, for example room temperature.

Bases such as tertiary amines such as triethylamine, diisopropylethylamine 4-dimethylaminopyridine, N-methylmorpholine or pyridine is required. Add mule.

Introduction of a divalent protecting group formed from one or two of the protecting groups x1 and X It is desirable to protect the hydroxyl group W1 present in formula (V) before Maybe.

A hydroxy group can be, for example, a -valent protecting group, e.g. an acyl group, e.g. a lower alkanoyl group. unsubstituted or substituted with a halogen, e.g. chlorine. , for example acetyl or 2,2-dichloroacetyl, or especially for protected amino groups. It may be protected by the acyl group of the carbonic acid half ester mentioned above. suitable hydro Oxy-protecting groups include, for example, 2.2.2-trichloroethoxycarbonyl, 4-nitrobene diphenyloxycarbonyl or diphenylmethoxycarbonyl. Hydroxy The group also includes tri-lower alkylsilyl, such as trimethylsilyl, triisopropropylene By pyrsilyl, tert-butyl-dimethylsilyl or especially dimethyl-( 2,3-dimethyl-2-butyl)silyl (=thexyldimethylsilyl), ether groups that can be easily separated, such as alkyl groups, such as [e lower alkyl, such as tert-butyl, oxa or thia aliphatic or cycloaliphatic , especially -2-oxa- or 2-thia aliphatic or cycloaliphatic hydrocarbon groups, such as l −Lower alkoxy, lower alkyl or! −lower alkylthio lower alkyl , for example, methoxymethyl, ■-methoxyethyl, l-ethoxyethyl, methylthi omethyl, l-methylthioethyl or l-ethylthioethyl, or 2-oxyethyl cer- or 2-thiacycloalkyl having 5 to 7 ring atoms, For example 2-tetrahydrofuryl or 2-tetrahydropyranyl or the corresponding by thia analogs, as well as 1-phenyl-lower alkyl, such as benzyl, diphthyl phenylmethyl or trityl (the phenyl group is unsubstituted or by a gene, such as chlorine, lower alkoxy, such as methoxy and/or nitro. (may be substituted).

The protected hydroxyl group is preferably lower alkoxycarbonyl or tri-lower alkoxycarbonyl. By rukylsilyl, especially trimethylsilyl, tert-butyl-dimethylsilyl dimethyl-(2,3-dimethyl-2-butyl)silyl or tert-butyl Protected by cyclocarbonyl.

If necessary, the hydroxyl protecting group is removed starting from formula CV') by methods known per se. Introduced into the material. Examples of suitable reaction conditions are, for example, J.

The above standard work of F, WoMe (laie and T, W, Greene) It is written inside.

For example, a tri-lower alkylsilyl protecting group can be replaced by a tri-lower alkylsilyl protecting group. The hydroxyl group in the compound of formula (V) is added to the protected hydroxyl group. Lower alkylsilyl halides, e.g. tri-lower alkylsilyl chloride By reacting with an inert solvent, e.g. lower alkyl cyanide, e.g. For example, in acetonitrile, a tertiary nitrogen base, such as 1,8-diazacyclo[5, 4,0]undec-7-ene between 0 and 50°C, especially between 15 and 30°C. Convert at temperatures between .

After introducing the amino protecting groups x1 and Xt, the hydroxyl protecting group is replaced with the amino protecting group. It can be cleaved from the corresponding amino protecting group of formula (Ill) without simultaneous removal.

retained by a suitable acyl group or unsubstituted or substituted l-phenyl-lower alkyl Protected hydroxyl groups are liberated analogously to the corresponding protected amino groups.

2. The hydroxyl group protected by 2-dichloroacetyl can be It is liberated by decomposition, and may be tert-lower alkyl or 2-oxa- or 2-thia-hydroxyl group protected by an aliphatic or monoalicyclic hydrocarbon group by acidolysis, e.g. mineral acids or strong carboxylic acids, e.g. trifluoroacetic acid. released by treatment with

tri-lower alkylsilyl, such as trimethylsilyl or dimethyl-(2,3- Dimethyl-2-butyl)silyl is preferably an alcohol, such as methanol or or cleaved by solvolysis with ethanol at temperatures between 20°C and reflux temperature. It will be done. The tri-lower alkylsilyl group is treated with a mineral acid, preferably hydrofluoric acid or a strong Acidolysis with carboxylic acids e.g. trifluoroacetic acid or liberating fluoride ions. Fluoride salts of metals or bases that release, e.g. acids of hydrogen fluoride and nitrogen bases Addition salts or metal fluorides, such as alkali metal fluorides, such as sodium fluoride Macrocyclic polyethers (crown ethers) with potassium or potassium fluoride reaction in the presence of organic quaternary bases, such as tetra-lower alkyl ammonium Umfluoride or tri-lower alkylaryl-lower alkylammonium Mufluoride, such as tetraethylammonium fluoride or tetrabutyl ammonium fluoride or N-pendylutrimethylammonium fluoride and aprotic polar solvents such as ethers, such as tetrahydrofuran. or dioxane, dimethyl sulfoxide or N,N-dimethylacetamide by reaction at a suitable temperature of about -20 to 50°C, e.g. Even if you do, you will be separated.

2-halo lower alkoxycarbonyl as a hydroxyl-protecting group is a reducing agent, For example, by reducing metals such as zinc, reducing metal salts such as chromium(11) salts, , or sulfur compounds such as sodium dithionite, or preferably sodium sulfide. removed by aluminum and carbon sulfide.

tri-lower alkylsilyl as a hydroxyl protecting group, as defined above. The introduction and removal of carbonic acid half-ester groups, especially lower alkoxycarbonyl It is particularly preferred when present as amino protecting groups X1 and X.

Compounds of formula (Ill) where Wl is a leaving group are, for example, compounds where Wl is hydroxyl. from a compound of formula (Ill) whose corresponding nuclear group, e.g. for example bromide or chloride, with aliphatic or aromatic substituents. such as lower alkanesulfonyl halides, such as meth sulfonyl chloride, or arylsulfonyl halide (e.g. -3o, -Cl-Br), where aryl has 6 to 14 carbon atoms , for example phenyl, naphthyl, indenyl or indanyl, and or by up to 3 groups, e.g. lower alkyl, e.g. methyl, lower alkyl, by oxy, e.g. methoxy, or halogen, e.g. fluorine, chlorine or bromine. For example, lower alkylphenylsulfonyl chloride (= lower class alkylphenyl-5Q 2-CI>, for example, p-toluenesulfonyl loride, substituted lower alkanesulfonyl halide, e.g. halo lower alkali trifluoromethanesulfonyl chloride, such as trifluoromethanesulfonyl chloride or reaction with hydrohalic acid, especially hydrogen chloride, hydrogen bromide or hydroiodic acid. If necessary, a suitable solvent such as a halogenated hydrocarbon, e.g. A tertiary nitrogen base, e.g. Lower alkyl amines, such as triethylamine or ethyldiisopropylamine absence of pyridine, pyridine or dimethylaminopyridine (e.g. hydrohalic acid between -78 °C and reflux temperature, especially -5 to 30 °C can be synthesized at a temperature of The above conditions are preferably halogen It is suitable for introducing a leaving group w1 excluding .

A halogen group is preferably a corresponding one in which wl is substituted by an aliphatic or aromatic group. compounds such as halides, especially metal halides, e.g. metal chlorides. , bromide or iodine, such as alkali metal chloride, bromide or For reaction with iosito or alkaline earth metal chloride, bromide or iosito in a suitable solvent, such as a di-lower alkyl ketone, such as acetone. , at a preferred temperature of -20°C to reflux temperature, e.g. 10-30'C. copper, for example in small pieces or as a powder in the case of yosemite. can be introduced in the presence of other things.

Amino protection must proceed via an intermediate of formula (v) with a free amino group. Synthesizing a compound of formula (Ill) directly protected by group X and/or x2 You can also

Thus, a compound of formula (III) in which: i is 1, and One of X, and X is hydrogen, and the other is hydrogen or a compound of formula (11) is a monovalent amino protecting group as defined for Compounds in which n is 0 or I are prepared by the conditions defined for compounds of formula (In): The following formula (fll): Y is a monovalent amino protecting group as defined above for Xt or is xycarbonyl, 8 is the same as defined for the compound of formula (1), and n' is 0 or l, With the help of Tadakoshi A and -(C=O)-(N-Y)~[(CH!),,]- The ring formed has 4 or 5 ring members, and (C=0)-(N-Y)-[(C H! ), , ]- The two bonds of the group do not originate from the same carbon atom of A. ) to The compound represented by It can also be done. Reduction resulting from simultaneous ring opening is preferably carried out using a suitable hydroxide. complexes such as aluminum hydride in ethers such as diethyl ether alcohol (preferably), such as methanol or ethanol sodium polyhydride in, or ether, e.g. in tetrahydrofuran dlsiaInylborane(bis(3-methyl-but-1-yl) According to Pollan), temperatures between -20°C and 50"C (7), especially between -5 and 25°C It will be carried out in . Y is X as defined above for compounds of formula (!■) , or X, especially as defined for lower alkoxycarbonyl Therefore, the corresponding compound of formula (III) where wl is hydroxyl can now be directly expressed as can be obtained.

The bond to the group is preferably in the cis configuration; the corresponding cis compound of formula (III) Get things later.

Compounds of formula (VII) are known or synthesized by methods known per se. be able to.

For example, a compound of the cis formula ml), in which: Y is a carbonate half ester acyl group as an amino protecting group, and 8 is a 1,3-cyclo A compound which is pentylene and n゛ is O, where Y is replaced by a hydrogen atom. Reacting 2-azabicyclo[2,2,1] with butan-3-one under conditions analogous to those defined above for the reaction of compounds of formula (1v). In the presence of 4-dimethylaminopyridine, the formula (m) as defined below Preferably (Y = tert-lower alkoxycarbonyl, e.g. terl-butoxycarbonyl), organic solvents, e.g. ethers, e.g. di- in the presence of a catalytic amount of 4-dimethylaminopyridine in lahydrofuran. 1erf - lower alkyl dicarbonate, e.g. diiert - butyl dicarbonate It can be synthesized by acylation with carbonate.

2-azabicyclo[2,2,1]butan-3-one is, for example, 2-azabicyclo[2,2,1]hebutan-3-one. By reduction of the double bond of chloro[2,2,1]hept-5-en-3-one, a special catalysts, such as palladium, platinum or in the presence of ruthenium, optionally under pressure, e.g. 1-10 bar. , in a suitable apparatus, such as a Parr apparatus, from 0 to 50°C, especially from 15 to 50°C. in a solvent, e.g. an ester, e.g. ethyl acetate, at a temperature of up to 30°C. It can be obtained by hydrogenation at 2-Azabishikuo[2,2,1]hept-5- xc3-one is, for example, 3-tosyl-2-azabicyclo[2,2,1] hepta-2,5-diene in a lower alkanoic acid such as acetic acid from O to 4 By reacting at temperatures up to 0°C, in particular between 15 and 30°C, the 3-tosyl-2-azabicyclo[2,2゜1]hepta-2,5- Dienes can be used, for example, at temperatures from O to 50°C, especially from 15 to 30°C. Obtained by cycloaddition of tosyl anide on cyclopentadiene.

Furthermore, the compound of formula ml) can be prepared by thermal or photochemical reaction of tosyl cyanide on the double bond. chemical cycloaddition and 3-tosyl-2-azabicyclo[2,2,1]hepta- A similar continuation of the synthesis as described for 2,5-diene yields can be done.

The following formula (VII[)’: )10-(CH!),-A"-(CHt),-NH-Y'(Vl ll) (in the formula, 3- to 6- in which Ao has one or more unsaturated bonds (excluding cyclobutanephenylene) a monovalent cyclic hydrocarbon as defined above for xl or an amino protecting group, especially lower alkanoyl, such as acetyl, or hydrogen; and other definitions and conditions similar to those for compounds of formula (1), provided that a) The distance between the -0H group and the Y''-HN- group is at least 3 and not more than 4 carbon atoms; b) Two groups -(CH, ), -OH and Y'-HN-(CI, ). − is not bonded to 80 identical carbon atoms. From the compound represented by l, the pair Compound of formula (III) (Y'/amino protecting group) or (V) (Y' = hydrogen) can be synthesized by reduction of the unsaturated bonds within its ring At. unsaturated The bond is preferably a double bond, and 80 is preferably a phenylene bond. , cyclopentenylene, cyclopentadiene, cyclobutenylene and cyclo selected from propenylene, especially phenylene.

The reduction is preferably carried out by hydrogenation using suitable catalysts, especially basic heavy metals or their oxides, such as nickel or cobalt (pressurized, e.g. 50-200 bar) Preferably alcohols, e.g. in ethanol or an aqueous alkali, e.g. an alkali metal hydroxide solution, e.g. , nickel or Raney nickel in aqueous sodium hydroxide solution), or precious gold or noble metal oxides, such as platinum, platinum oxide, palladium, palladium oxide or Ruthenium (preferably an alcohol, such as methanol or ethanol, alcohol) esters, such as ethyl acetate, ethers, such as dioxane, and water. in a suitable solvent, or in a suitable mixture of said solvents; lower alkanoic acids, e.g. In the presence or absence of acetic acid, or under basic conditions, the above catalyst is combined with a support material, e.g. , activated carbon, barium sulfate, strontium sulfate, calcium carbonate, aluminum oxide um or silica gel: a suitable temperature, especially 0 and 50° C., e.g. at room temperature; optionally under pressure, e.g. and 20 bar).

Similar to the hydrogenation of the compound of formula (Vlll), -Nil-Y' is substituted by a nitro group. It is also possible to hydrogenate analogous compounds prepared by For example, in sodium hydroxide solution under a pressure of 50 to 80 bar and 150 to 19 Performed with Raney nickel at a temperature of 0°C.

The corresponding compounds of formula (V) are obtained directly.

The compound of formula (fl　　[) is known or can be synthesized by a method known per se. In the case of similar compounds in which -Nil-Y' is substituted by a nitro group, The same is true.

A compound of formula (1■) can be synthesized, for example, as follows: X, or When X is a -valent amino protecting group, e.g. an acyl group as defined above, the free Hydroxyamines or salts thereof have x, ° and x, ° as amino protecting groups. is the acyl defined earlier. ) or can be synthesized by reaction with their activated derivatives, which also For acylation of amino groups in situ and for example as mentioned above and below. formed by conventional methods for the introduction of protecting groups such as those described in standard procedures. can be X, l and X, l are, for example, lower alkanoyl or is unsubstituted or substituted benzoyl, hydroxyl of formula (1x) or <XX) An activated hydroxyl group in which the syl group is replaced by an activated hydroxyl group is For example, acyloxy, where acyl is preferably X, l or xlo same as or other than azide, azolide, e.g. zolides, halogens, e.g. chlorine or bromine, or nitrophenoxy, e.g. acid anhydrides, acid azides or acid halides, especially the corresponding acid chlorides. activated acid In situ synthesis of derivatives, such as carbodiimides, e.g. Lower alkyl- or N, N'-diC=-Ct cycloalkyl-carbodi imide, such as diisopropylcarbodiimide or N,N'-dicyclohexyl By reaction in the presence of a silcarbodiimide, an activated catalyst, e.g. N-hydroxysuccinimide or N-hydroxybenzotriazole unsubstituted or substituted with halogen, lower alkyl or lower alkoxy It takes place in the existence of something. bases, e.g. tertiary amines e.g. triethyla amine, diisopropylethylamine, dimethylaminopyridine, N-methylmol Folin or pyridine is added if necessary. X, l or x, l are carbonic acid When it is a half-ester group, the hydroxyl group in X, 1 or x, 1 is preferably or of formula (IX) or (XX) as an activated hydroxyl group as defined above. in particular, the hydroxyl group is subsequently replaced by a halogen, e.g. chlorine. or bromine, or substituted by an azolyl group, such as imidazoyl.

An alkylformimidoyl group X, or x4 in the hydroxyamine, e.g. Me in J. Am. Chew, Soc. 106.3270 (1984) Yers, A. et al.

was introduced by a method similar to that described by A lumimidoyl group, for example, N. free hydroxyamine.

N-dimethyl-N'-tert-butylformamidine and triturate at reflux temperature. by reacting in the presence of a catalytic amount of ammonium sulfate in toluene or Alternatively, tert-butylformamide and methyl chloride of EtsO+BP, Addition of amino compounds and reaction from room temperature to 40 °C by reaction at room temperature in is introduced by further reaction within the temperature range of .

hydroxyamine disulfonic acid (x, and x, = sulfo in the compound of formula (m), and especially its alkaline earth metal or ammonium salts, e.g. Dorit concentrated solution and alkali metal hologen sulfate or corresponding ammonia It is synthesized by reaction with aluminum salt and sulfur dioxide.

Arylmethyl X and/or x4 in the compound of formula (m) is, for example, hydroxy Amines and arylmethyl halides, especially arylmethyl chlorides or Preferably, a tertiary amino acid is formed by reaction with romide by nuclear substitution of a halogen atom. in the presence of an aprotic solvent such as triethylamine or pyridine. , ethers such as tetrahydrofuran or dioxane, or carboxylic acid amide reaction in di-lower formamide, e.g. dimethylformamide. It is introduced by.

When both X and X in the compound of formula (1■) are divalent amino protecting groups, The following synthetic methods are preferred for the synthesis of these starting compounds: Oxime derivatives of formula (IVa) (X,,,)・N-OH(IVa) In one set, X Iz as defined above for compounds of formula (11) in the case xS and X It is a divalent mono- or di-substituted methylidene group such as the above. ) is the corresponding aldehyde or a ketone intermediate, where =N-OH in formula (IVa) is double bonded oxygen (:0) Under conditions customary for the reaction of aldehydes or ketones with amino compounds, With roxyamines, preferably in particular inorganic acids, such as hydrohalic acids, e.g. For example, hydrochloric acid, sulfuric acid, e.g. as sulfate or hydrogen sulfate, phosphoric acid , for example as phosphate, hydrogen phosphate or dihydrogen phosphate, organic acids, e.g. For example, lower alkanoic acids containing norogens in the lower alkyl group, such as fluorine, salts, etc. or preferably unsubstituted, e.g. vinegar acid, chloroacetic acid, dichloroacetic acid or trifluoro- or trichloroacetic acid, sulfonate acids, such as lower a/monosulfonic acids, such as methane- or ethanesulfonic acids. acid or ethanedisulfonic acid, or aromatic sulfonic acids, such as benzene- or as a salt with naphthalenesulfonic acid or naphthalene-1,5-disulfonic acid; is a double salt, for example, Zn(NH*OH)tC1t (Crismers test in the form of drugs), from which it is substituted; The corresponding aldehyde or ketone and water, an aqueous mixed solvent, e.g. water and alcohol , for example, mixtures with methanol or ethanol, di-lower-alkyl sulfonate chito, e.g. dimethyl sulfoxide, or di-lower alkyl-lower alkano ylamines, e.g. dimethylformamide, or organic solvents, e.g. the last mentioned. or sufficiently inert nitriles, e.g. acetonitrile, mixtures thereof. in a compound or liquid ammonia, preferably in an aqueous alcoholic solution, e.g. in ethanol/water or ethanol/water; preferably between -78°C and reflux temperature from -30°C to 100°C, in particular from 5 to 90°C, for example about 80°C. At a temperature in °C: in the absence of a base or preferably a hydroxyamine In the case of acid salts of bases, especially hydroxides, e.g. acids, such as sodium hydroxide or potassium hydroxide, carbonates or bicarbonates, especially an alkali metal carbonate or bicarbonate or an alkaline earth metal carbonate or bicarbonate, For example, sodium carbonate or potassium carbonate or sodium bicarbonate or potassium bicarbonate. salts of weak organic acids, especially alkali metal salts of lower alkanecarboxylic acids, e.g. Sodium acetate or potassium acetate, organic nitrogen bases, especially sterically hindering (secondary or secondary) 3) amines, e.g. pyrrolidone or pyridine, or anion exchange groups, e.g. , Amberl! te@IR-411, and alkali metal carbonate under acid buffer. can be synthesized with particular preference for the presence of

A hydrocarbyl dicarboxylic acid derivative of the formula (lVa), in which X Ill is the formula X in the compound (Iz), and both carbonyls as defined above for X. A hydrocarbyl dicarboxylic acid group bonded via a group is, for example, Hydroxyamine and its corresponding free hydrocarbyl dicarboxylic acid with its hydrocarbyl dicarbonyl group, or a reactive derivative thereof; It can be synthesized by reaction. Reactive derivatives include, for example, the corresponding dicarboxylic dicarboxylic acid anhydride, dicarboxylic acid diazide or dicarboxylic acid civalide, in particular the corresponding dicarboxylic acid dichloride, or the corresponding intramolecular dicarboxylic acid anhydride (oxa two carbonyl groups bonded via) or a reactive derivative formed in situ compounds of formula (1x) and (X) in reaction with hydroxyamines, e.g. was synthesized as previously described for. This reaction is preferably carried out by the formula Conditions similar to those described above for the reaction of compounds (1x) and (X) occurs in Corresponding carboxylic diesters, e.g. di-lower alkyl dicarboxylate - Esters, such as dimethyl or diethyl dicarboxylate esters and hydro Amino acid transfer with xyamine is also possible.

Compounds of formula (V) are commercially obtainable, known or prepared by methods known per se. can be synthesized more easily.

For example, compounds of formula (V) can be prepared by the methods described above, where Yo is hydrogen or other as defined. or from a compound of the formula (Vll) substituted by a group of The reaction of analogues of compounds of formula (Vll) as defined above results in compounds of formula (Vll) ) was synthesized under the above conditions for the reduction and cleavage of the amide bond within the compound can be done. A compound of formula (V), During the ceremony, ^ is Cs-CI cycloalkylene (especially 1,3-cyclobutylene), The theory is 1, n is 0 or l, especially 0; However, a) the distance between the group -W,' (hydroxyl) and the group N, H- is at least 3 and 4 or less carbon atoms, and b) two groups, -(CHx), - w+” and NtH−(CHt)−1 are not bonded to the same ring atom of A. In particular, a compound with the following formula (Xl): H2C=(A”)-[(CH#)@ , 1-NHXI” (XI) (wherein, A6'' is C, -C, cycloalkan-yl-ylidene, especially cyclobutane-1- yl-3-ylidene, nl is O or l, especially 0, and X, 11 are tert-lower alkoxy carbonyl, e.g. [e"[-butoxycarbonyl, or phenyl-1-lower a) benzyloxycarbonyl, with the proviso that the group a) The distance between H, C=(methylidene) and the group and 3 or less carbon atoms, and b) two groups H, C. and -[(CHt). , .]- is not bonded to the same ring carbon atom of A. )yo From the compound represented by More preferably, by BH, in an ether, such as tetrahydrofuran. , sodium borohydride (s) in diethylene glycol dimethyl nityl odiu borohydride) and boron trifluoride ether or by lower alkanoic acids, such as acetic acid, ethers, such as tetrahydride. Sodium boron in Lofuran allows the temperature between O and 40°C, especially between 0°C and room temperature. and by subsequent alkaline oxidation. Ammonium chloride or alkali metal hydroxide, such as sodium hydroxide or hydroxide With an aqueous solution of potassium and hydrogen peroxide, between 0 and 50°C, especially between 15 and 3 converting the methylidene group to a hydroxymethyl group at a temperature between 0°C; Combine while simultaneously separating XS. In a preferred embodiment, XI is not separated, and xl is replaced by the last defined XS, making XI is substituted with hydrogen, the compound of formula (Ill) is substituted with hydrogen, and the other group is replaced with hydrogen. Obtained while keeping the same as defined for the object.

radicals as defined, especially when 8- is cyclobutan-1-yl- Compounds of formula (XI) which are 3-ylidene and nl is O or 11 especially O For example, the following formula (Xll): H*C(A”)-[(CHt)1.]-COOH(Xll) (in the formula, 8- is C, -C, cycloalkan-yl-ylidene, especially cyclobutan-1-ylidene Ru-3-ylidene, n" is 0 or l, especially 0, However, a) the distance between the group H*C (methylidene) and the group -COOH is at least up to 2 and 3 carbon atoms, preferably b) two groups H, C= and HOOC-[ (CH*) 1. ]- is not bonded to the same carbon atom of A. ) carboxylic acids of formula (Xll) or lower alkanoic acids, e.g. For example, their activated acid derivatives with acetic acid, such as acid halides or anhydrides, can be synthesized by known methods), azide salts, e.g. alkali converting a metal azide, such as with sodium azide, to its acid azide; and add them (preferably under reflux) to a tertiary alkanol, e.g. Tanol or phenyl-1-lower alkanol, e.g. benzyl alcohol by reacting in the alcohol; preferably in the alcohol under reflux. By reaction with azide of a phosphoric acid azide, e.g. diphenylphosphoryl azide By direct synthesis of acid azides in situ; Synthesize by rearrangement and formation of one group.

WIo is hydroxyl, ^ is C, -C, cycloalkylene, especially 1,3-cyclobutylene, and n is 1 and A compound of formula (v) where m is 0 and has the above conditions is represented by the following formula (Xllll) : N=C-(A"")=0(Xllll) (in the formula, A08 is Cs-Cs cycloalkan-yl-ylidene, especially cyclobutane- 1-yl-3-ylidene, provided that a) between the cyano group and the oxo group (:0) b) the distance between the two groups is at least 2 and not more than 3 carbon atoms; and N=C- is not bonded to the same carbon atom of A. ) - from nitrile compounds by simultaneous or stepwise reduction of their cyano and keto groups, e.g. For example, in an ether such as diethyl ether or tetrahydrofuran, Suitable hydride complexes, such as lithium aluminum hydride (with simultaneous cyano groups) ), LiAIH[0C(CI+3)s]s or bis(3-methyl-but-2-yl)borane (dicyamylborane(dis) by the first reduction of the keto group by iaw + ylborane)); with sodium hydrogenide or sodium cyanoborohydride, optionally in the presence of LiCl. in water or alcohol, e.g. lower alkanols or lower alkanediols , for example in methanol, ethanol or ethylene glycol; between 0 and 50°C. at temperatures between, for example between 25 and 40°C; and (if necessary) cyano Subsequent reduction of the group, e.g. with a suitable heavy metal catalyst, e.g. Raney nickel. in the presence of an alcohol, such as methanol or ethanol, preferably ammonia. between 0 and 50° C., e.g. in the presence of 1 to 15% by weight ammonia. For example, it can also be synthesized at temperatures between 25 and 40°C.

Ketonitriles of formula (Xl11) are known or can be synthesized by methods known per se. can be accomplished. For example, 3-oxocyclobutanetriponitrile is - methylenecyclobutanecarbonitrile with water and ethers, e.g. diethyl in a mixture of ethers at temperatures between 0 and 30°C, especially between 5 and 10°C. The addition of osmic acid and alkali metal metaperiodates, e.g. Due to the slow addition of um metaperiodate, preferably an inert gas, e.g. Under nitrogen, filtrate with a water valve compatible organic solvent, e.g. halo lower alkanes, e.g. Washing with chloroform, evaporation of the organic phase, ether, e.g. tetrahydro Dissolution of the residue in furan, addition of mercury carbonate and silver, standing under reflux and protection from light. protection, evaporation of ether and evaporation of the corresponding product of formula (X[I+) in the vacuum of an oil pump. It can be synthesized by distillation. 3-methylenecyclobutanecarbonitrile is obtained by cycloaddition of arenes (propanedienes) on acrylonitrile. (Cripps, H, N, et al, in J, Ag, ChetSoc, 81.2723-28 (1959)).

A is the same as defined for compounds of formula (summer), especially l.

2-cyclopropylene, The cabinet is 1, n is 1, and A compound of formula (v) in which Wl' is hydroxyl and has the above conditions, For example, the following formula (XIV): N=C-[(CHw)--+]-A-[(CHw)m-11-CO oG (XIV) (wherein, is the same as defined by A, G is lower alkyl, such as methyl or ethyl, aryl, such as phenyl, naphthyl or fluoren-9-yl, or aryl-lower alkyl, e.g. phenyl-, naphthyl- or fluoren-9-ylmethyl, and n and l are the last defined, provided that a) the combination of a cyano group and -COOG group The distance between them is 2 carbon atoms. ) is a cyanocarboxylic acid ester represented by upon simultaneous or stepwise reduction of its cyano and keto groups to its corresponding compound of formula (V). For example, ethers such as diethyl ether or tetrahydrofuran suitable hydride complexes, such as lithium aluminum hydride (preferably (Also allows simultaneous reduction of cyano groups) or! , 1AIH[0c(CHr )　s　　s　　s　+,: Ester group (-COOG) (7) First reduction nitrogen : or especially with sodium borohydride, optionally in the presence of LiCl. For example, lower alkanols or lower alkanediols, such as meth in alcohol, ethanol or ethylene glycol; between 0 and reflux temperature, especially reflux temperature. at flow temperature; or with an alkali metal, e.g. sodium, in alcohol. , e.g. in ethanol; and (if necessary) subsequent reduction of the cyano group, e.g. For example, in the presence of a suitable heavy metal catalyst such as Raney nickel, an alcohol, e.g. e.g. between 0 and 50°C, e.g. 25 and 40°C, in methanol or ethanol. or ester groups to hydroxymethyl groups, and cyano groups at temperatures between; to the aminomethyl group of,! The hydrogenation occurring in batches allows suitable catalysts, especially Basic heavy metals or their oxides, such as nickel or cobalt (preferably , at temperatures from 150 to 190 °C under pressure, e.g. 50 to 200 bar. nickel or Raney nickel in an alcohol, e.g. ethanol) , or noble metals or noble metal oxides, such as platinum, platinum oxide, palladium, palladium oxide, etc. or ruthenium (preferably an alcohol, such as methanol or ethyl alcohol) selected from alcohols, esters such as ethyl acetate, ethers such as dioxane. in a suitable solvent, or in a suitable mixture of said solvents; preferably, excess amperage In the presence of ammonia, for example from 1 to 15% by weight, the catalysts described above are suitable supports. holding materials such as activated carbon, barium sulfate, strontium sulfate, calcium carbonate , while allowing it to be bonded to aluminum oxide or silica gel; preferred temperature, in particular between 0 and 50°C, e.g. room temperature; if necessary under pressure , e.g. below between about 1 and 20 bar). can be synthesized in

The compound of formula (Xm is known or can be synthesized by a method known per se) Can be done. For example, a compound of formula (Xm, where: A is 1,2-cyclopropylene and G is ethyl (ethyl 2-cyanosyl) (chloropropane carboxylate) on acrylonitrile. Cycloaddition of ethyl diazoacetic acid (N2CH-CO-OEt) (for example, ethyl diazoacetic acid (N2CH-CO-OEt) 2 to 3 times the molar amount with respect to zoacetate), preferably at elevated temperatures. Distillation of excess acilonitrile under reflux to a temperature between 120 and 170°C. Synthesis can be achieved by further heating thereafter.

Other starting materials are commercially available or known or by methods known per se. be synthesized.

Additional method treatment of the formula (+) can be obtained by a defined method and has salt-forming properties. The free compounds can be converted into their salts in a manner known per se; Since these are basic compounds, this can be done by acids or suitable derivatives thereof. Processing can be done by:

The compound of formula (11) may be further used for purification purposes (e.g. in pure form, e.g. , (S) or (R) configuration) (for separation of protected diastereomers or enantiomers) from a compound of formula (1) It can also be prepared. The purified compound of formula (+) is then prepared as described above. This is done by removing the protecting group as described above.

Isomal mixtures of compounds of formula (1) which can exist in several isomeric forms The compounds can be separated into the individual isomers by methods known per se.

The cis or trans isomers or both can be separated by conventional methods. It can be obtained in pure form from a mixture of its sexes.

Suitable methods for the removal of one isomer or for the separation of two isomers are e.g. For example, chromatographic methods, e.g. adsorption chromatography on silica gel an organic solvent or mixed solvent, such as a hydrocarbon, such as a liquid lower alkali. esters, such as pentane, hexane or heptane, or esters, such as lower by alkyl-lower alkanoates, such as ethyl acetate, or mixtures thereof. What is to be eluted, if necessary, an immiscible solvent, such as water and a water valve compatible organic solvent, For example, between halogenated hydrocarbons such as methylene chloride or chloroform Polyhedral or fractionated crystals, e.g. organic solvents, e.g. aromatics, e.g. benzene , from solution in toluene or xylene, optionally pure cis Or seeding by transformer.

Mixtures of enantiomers are, for example, characterized in that individual enantiomers are preferably Scientifically pure salt-forming reagents, such as (S,S)- or (R,R)-tartaric acid, ( R)- or (S)-lactic acid, 1(R)- or 1(S)-camphorsulfonic acid or By salt formation with (L)-glutamic acid, dia Resolution of stereomeric mixtures can be achieved, for example, by fractional crystallization and/or by enantiomeric Mer resolution can be achieved by mechanical harvesting of optically active protecting groups with asymmetric centers, e.g. , (S)-1-phenylethyl and the resulting diastereomer The resolution can be carried out, for example, by fractional crystallization, preferably by chromatography, e.g. , by fractionation or adsorption chromatography, or by fractionation in multilayer solvent mixtures. , and removal of protecting groups as previously described, or optically active column materials, For example, optically active quartz, cellulose, optically active ion exchange groups, aminopropyl - D-dinotrobenzoylphenylglycine (P) covalently bonded to silica gel irkle phase), D-3,5-dinitrobenzoylph bound to silica gel enylglycine, or endiomerically pure covalently bonded to silica gel. Chromatography on amino acids such as (L)-valine or (L)-proline In convenient and appropriate cases, also in the form of copper complexes, be able to.

Materials that allow selective synthesis of individual isomers of compounds of formula (+), e.g. pure Especially starting from formula (11), cis or trans isomerically or enantiomerically pure The material is preferably used directly.

The salts of the free compounds of formula (+) can be prepared in a manner known per se in a suitable solvent, e.g. water, alcohols, e.g. methanol, ethanol, e.g. diethyl ether acids, such as inorganic acids, such as hydrogen chloride, or a mixed solvent thereof. acids or sulfuric acids, organic carboxylic acids, such as adipic acid, or organic sulfonic acids, such as For example, benzenesulfonic acid, or a suitable anion loaded with an amion of the corresponding acid. can be synthesized by treatment with an exchange reagent. Salt is its free form The compound is treated in conventional manner, for example with a suitable base agent, such as hydrochloride in free solution. loaded with xybases, e.g. alkali metal hydroxides, or hydroxides By treatment with anion exchange groups, e.g. chromatography or batch processes can be converted by

The conversion of the salt of the compound of formula (1) is carried out by the synthesis of the free compound and as described just above. This can be carried out by subsequent conversion to its acid addition salt, as described above.

The acid addition salt of one of the compounds of formula (1) and the acid addition salt of the compound of formula (1) and the other Direct conversion to an acid with a second fresh acid is also possible.

This conversion preferably comprises: a) converting the original acid addition salt in free solution into a suitable amount of new acid; , for example by reacting in the presence of excess; or b) by reacting in the presence of an excess of It is carried out on an anion exchange group loaded with ions.

In addition, the gel chromatography salt conversion method converts the acid addition salt of the base of formula (1) into other acid addition salt or converting the free compound or free base to its corresponding acid It can be used for any reaction that is useful.

Other salts of the free compound or salts, preferably halides, e.g. chlorides, e.g. For example, conversion to a halide, e.g. In the case of salts of acids, such as sulfates, in particular the crystalline salts of the compound of formula (1) are such It is particularly preferred in the case of the free compound or salt when it is obtained in the form of a salt.

General reaction conditions Closeness between starting materials with salt-forming groups in free form and those in salt form As a result of the relationship, and also the compound of formula (+) in the free form and in the salt form As a result of the close relationship between the above and below corresponding liberated The compounds or their salts are conveniently and suitably their corresponding salts or free starting materials. It should also be understood as meaning a material or a compound of formula (1).

If acid groups are present in the starting material, e.g. sulfo or carboxyl groups, e.g. For example, salts with bases, for example metal salts, such as alkali metal or alkaline earth metals. salts such as sodium, potassium, magnesium or calcium salts, ammonia salts with nitrogen bases, such as quaternary nitrogen compounds, such as tetra- Lower alkylammonium compounds, etc. may be present. base group present For example, when the salt is an acid addition salt mentioned in the definition of the salt of the compound of formula (1) can exist similar to.

Compounds according to the invention with their salt-forming base groups may be used depending on the procedure and reaction conditions. Depending, it can be obtained in free form or in salt form.

Compounds including their salts can also be obtained in the form of their hydrates, or These crystals can, for example, contain the solvent used for crystallization.

Hydrates are formed from the resulting compound, e.g. by leaving it in the air. It can also be done.

Functional groups not intended to participate in the reaction, especially amino and hydroxyl groups, It is present in the starting material in optionally protected form. Protecting groups, especially amino- and and hydroxyl-protecting groups, if necessary, by methods known per se (e.g. of formula (II+)) is introduced into the starting material. Examples of suitable reaction conditions include, for example, J, F., W., and McOmie.

”Protective Group in Organic Che+n1s try”, PIenuInPress, London.

New York, 1973. and T. W. Green, “Protecti. ve Grouos in Organic Synthesis', Will Described in the standard work by E.Y., New York, 1984. There is. The amino group to be protected can only be protected within the context of what is chemically possible. It can be simultaneously protected by a protecting group. Preferably only one monovalent or Only one divalent protecting group is present within the protected amino group.

Free the protected intermediates that can be obtained or use them further without removing the protecting group. can be done. Here, the introduction, the nature of the protecting groups used and their removal are as follows: Similar to those mentioned earlier or later.

an asymmetric center is present in the protecting group and the group is enantiomerically pure In some cases, for example, (S)-phenyl-lower alkyl-methyl, such as 1(S )-phenylethyl, the corresponding diastereomer of the intermediate is Siomerically pure intermediates or nansiomerically pure compounds of formula (1) by resolution of these diastereomers, e.g. in organic solvent mixtures, e.g. , (benzene or toluene) badiethyl ether or dioxane) Chromatography on silica gel using alkyl ketones (e.g. acetone) Can be used to obtain by roughy.

If necessary, the hydroxyl group, e.g. hydroxyl W l, can be placed in the protected form. similar to the amino protecting groups already mentioned, the corresponding protecting groups can be present in one or divalent (in the latter case, hydroxyl and amino are held together) can also be protected, i.e., for example, ■ or 2 amino protecting groups L, X t, Xs and X.

can each protect the hydroxyl group by their second bond. ) .

A hydroxy group can be, for example, a -valent protecting group, e.g. an acyl group, e.g. a lower alkanoyl group. unsubstituted or substituted with a halogen, e.g. chlorine. , for example acetyl or 2,2-dichloroacetyl, or especially for protected amino groups. It may be protected by the acyl group of the carbonic acid half ester mentioned above. suitable hydro Oxy protecting groups are, for example, 2.2.2-trichloroethoxycarbonyl, 4-nitro Benzyloxycarbonyl or diphenylmethoxycarbonyl. hydroki Syl groups can also be tri-lower alkylsilyl, such as trimethylsilyl, triisopropylsilyl, etc. By lopylsilyl, tert-butyl-dimethylsilyl or especially dimethyl- (2,3,-dimethyl-2-butyl)silyl (=thexyldimethylsilyl), - Tellifying groups that can be easily separated, such as alkyl groups, such as te rt-lower alkyl, such as tert-butyl, oxa or thia fatty or Cycloaliphatic, especially -2-oxa- or 2-thiaaliphatic or cycloaliphatic hydrocarbon radicals, e.g. For example, l-lower alkoxy lower alkyl or l-lower alkylthio lower a methoxymethyl, l-methoxyethyl, l-ethoxyethyl, methoxyethyl, thylthiomethyl, l-methylthioethyl or 1-ethylthioethyl, or 2 -oxa- or 2-thiacycloalkyl having 5 to 7 ring atoms 2-tetrahydrofuryl or 2-tetrahydropyranyl, or by the corresponding thia analogs, as well as 1-phenyl-lower alkyl, e.g. benzyl , diphenylmethyl or trityl (the phenyl group is unsubstituted or halogens such as chlorine, lower alkoxys such as methoxy and/or nitro may be protected by (may be replaced by).

Hydroxyl and amino groups occurring simultaneously within one molecule can be treated as, for example, divalent protecting groups, For example, an unsubstituted or preferably lower alkyl group, e.g. By a methylene group substituted by For example, lower alkylene, such as isopropylene, cycloalkylene, such as -protected by cyclohexylene, carbonyl group or phenylmethylene can be done.

The protected hydroxyl group is preferably lower alkoxycarbonyl or tri-lower Alkylsilyl, especially trimethylsilyl, tert-butyl-dimethylsilyl, Dimethyl-(2,3-dimethyl-2-butyl)silyl or tert-butoxyca protected by rubonyl.

protected by a suitable acyl group or unsubstituted or substituted l-phenyl-lower alkyl The hydroxyl group is released in the same manner as the corresponding protected amino acid. 2.2-Dichloro Hydroxyl groups protected by loacetyl can be decomposed by, for example, base hydrolysis. and tcrt-lower alkyl or 2-oftha- or 2-thia-lipid Hydroxyl groups protected by aliphatic or -cycloaliphatic hydrocarbon groups can be treatment with mineral acids or strong carboxylic acids, e.g. trifluoroacetic acid. released by

Divalent protecting groups, preferably e.g. lower alkyl, e.g. Methylene groups mo- or di-substituted by lene, e.g. isopropylene, silane By chloroalkylene, e.g. cyclohexylene, or phenylmethylene, - Hydroxyl and amino groups that occur simultaneously within a protected molecule are particularly important for mineral acids. Alternatively, it can be released by acid solvolysis in the presence of a strong organic acid.

tri-lower alkylsilyl, such as trimethylsilyl or dimethylsilyl-( 2,3-dimethyl-2-butyl)silyl is preferred. With Solvolisil, For example, with an alcohol, such as methanol or ethanol, at 20°C and reflux. At temperatures between temperatures, they can be pulled apart. Also, Tory lower alki The lucilyl group is susceptible to acid hydrolysis with mineral acids, especially hydrofluoric acid, or strong carboxylic acids. or metal fluorine salts or bases that liberate fluoride ions, e.g. fluorinated water. acid addition salts and nitrogen bases or metal fluorides, such as alkali metal fluorides. macrocyclic polymers, for example by reaction with sodium fluoride or potassium fluoride. in the presence or absence of a riether (“crown ether”) or an organic quaternary base fluoride, such as tetra-lower alkylammonium fluoride or tetra-lower alkylammonium fluoride. lower alkylaryl-lower alkylammonium fluoride, e.g. Tetraethylammonium fluoride or tetrabutylammonium fluoride By lido, aprotic, polar solvents such as ethers, e.g. tetrahydro Furan or dioxane, dimethyl sulfoxide or N,N-dimethylacetamide at a preferred temperature of about -20 to 50°C, e.g. between 0°C and room temperature. At temperatures between, they are separated.

2-halo lower alkoxycarbonyl as a hydroxyl protecting group is a reducing agent, For example, by reducing metals such as zinc, reducing metal salts such as chromium(11) salts, etc. or sulfur compounds, such as sodium dithionite or, preferably, Removed by thorium sulfide and carbon disulfide.

Esterified hydroxyl groups, e.g. lower alkanoyloxy, e.g. acetyloxy Ruoxy can also be released by esterases.

The hydroxyl group, for example, simply separates the cis and trans versions of formula (1) from each other. It can also be protected for the purpose of This is especially true for tri-lower alkyl Adding a silyl protecting group to a compound of formula (II+) and a corresponding protecting group to a compound of formula (V) This is done by introducing under the conditions mentioned for introduction. For example, preferred Alternatively, chromatography on silica gel using a suitable solvent or mixture of solvents as eluent After subsequent resolution of the cis/trans isomers by tography, the hydroxy The protecting group is again separated from the resolved isomer as described above.

The above-mentioned reactions are carried out under reaction conditions known per se and using a solvent or diluent, preferably is inert to the reagent used and dissolves or suspends it, but is absent (reagent the drug, e.g. when it itself serves as a solvent or is present as a melt) or in the absence or presence of catalysts, thickeners or neutralizing agents, and Decreased, normal or increased, depending on the nature of the reaction and those participating in the reaction. at a temperature of, for example, about -80°C to about 200°C, preferably about - within a temperature range of 20°C to reflux temperature, e.g. about θ to 30°C, or reflux temperature in a pressurized atmosphere or in a closed container, suitably under pressure or in an inert atmosphere. in an ambient atmosphere, for example under an argon or nitrogen atmosphere, conveniently and If appropriate, block out the light and select suitable parameters from those listed above. However, there are many things that can be done. Certain reaction conditions specifically mentioned are preferred.

Solvents and diluents include, for example, water, alcohols, e.g. acids such as methanol, ethanol or propatool, diols such as Ethylene glycol, triols such as glycerol, or aryl alkaline Coles, e.g. phenols, acid amides, e.g. carboxylic acid amides, e.g. dimethylformamide or dimethylacetamide, or 1,3-dimethyl-3, 4,5,6-tetrahydro-2(IH)-pyrimidinone (DMPU), or inorganic Amides of acids, such as hexamethylphosphoric triamide, ethers, such as cyclic ethers, ethers, such as tetrahydrofuran or dioxane, or non-physical ethers, e.g. For example, diethyl ether or ethylene glycol dimethyl ether, ha halogenated hydrocarbons, such as halo lower alkanes, such as methylene chloride or loloform, ketones such as acetone, nitriles such as acetonitrile, Acid anhydrides, such as acetic anhydride, esters, such as ethyl acetate, bisalkanes rufins, e.g. dimethyl sulfoxide, heterocyclic nitrogen compounds, pyridine, carbon Hydrogenides, such as lower alkanes, such as heptane, or aromatics, such as benzene. zene, toluene or xylene, or mixtures of these solvents, with particular preference A suitable solvent can be selected for the reaction described above.

Conventional methods may be used to prepare the compounds of formula (1) or their salts that can be obtained. For example, solvolysis of excess reagent; recrystallization; chromatography , e.g. fractionation, ionic or gel chromatography; between inorganic and organic solvent phases fractionation; single or multiple extractions, especially after acidification or increasing the basic or salt content drying on hygroscopic groups; digestion; filtration; washing; dissolution; evaporation (if necessary, (in air or under high vacuum); distillation; e.g. in the form of an oil or its mother liquor; crystallization of a compound obtained from used for or repeatedly used; A combination of two or more of the above-mentioned preparation steps may be used, such as.

The starting materials and intermediates are in pure form, e.g. after preparation, as just mentioned. , in partially purified form, or directly as a crude product, e.g. can be done.

Isomers, such as cis/trans isomers or enantiomers, are at any suitable stage in the synthesis of the compound, at the intermediate stage or can be divided or split at any stage of the final product. used here The method to use is described above under AdditionalProcess Measure. on the method described in or General Reaction Conditions Similar to the method in section . Only isomerically pure starting materials directly You can also use

Methods similar to those described in the examples include the preparation of both starting materials and final products. Particularly preferred for.

The invention relates to compounds that can be obtained as intermediates in any process step. is used as a starting material and the remaining process steps are carried out or such that the compound is formed under the reaction conditions or is used in the form of a derivative, e.g. a salt thereof. It also relates to aspects of the eel process.

pharmaceutical composition The present invention provides a pharmaceutical composition comprising, as an active ingredient, a pharmaceutically acceptable formula (1 ) or a pharmaceutically acceptable salt thereof.

Compositions for enteral, especially oral, and parenteral administration are particularly preferred. This composition is , an active ingredient, alone or preferably together with a pharmaceutically acceptable carrier. It consists of The dosage of the active ingredient depends on the disease and species to be treated, age, body weight, skin level. depending on the product and individual condition, as well as the mode of administration.

The pharmaceutical compositions comprise from about 5x to about 95% active ingredient, and a single dosage form comprises: The dosage form preferably comprises from about 20% to about 90% and is not a single dose. preferably contains from about 5x to about 20% active ingredient.

Dosage unit forms, e.g. coated tablets, tablets or capsules, from about 0.01 g Up to about 2g, preferably from about 0.05 to about 1.0g of active ingredient, especially 0.0g. Contains from 1 to 0.6g.

The present invention provides for the treatment of diseases that respond to the inhibition of ODCs, in particular the diseases mentioned above. For the preparation of a pharmaceutical composition for use as an ODC inhibitor, the formula (1 ) also relates to the use of the compounds.

The pharmaceutical compositions of the invention can be prepared in a manner known per se, e.g. by conventional mixing, granulation. , coating, dissolving or freeze-drying. child Pharmaceutical compositions for oral administration, such as, combine the active ingredient with one or more solid carriers. combined, suitably granulated the resulting mixture, and suitably additional excipients. The mixture or granules can optionally be prepared into tablets or coated tablet cores. It can be obtained by processing.

Suitable carriers are in particular fillers such as sugars such as lactose, sucrose. , mannitol or sorbitol, cellulose preparations and/or calcium phosphate, For example, tricalcium phosphate or calcium hydrogen phosphate, and also a binder. , for example starches such as corn, wheat, rice or potato starch, methylcellulose , hydroxypropyl methylcellulose, and/or optionally a disintegrant, e.g. For example, the starches mentioned above, and also carboxymethyl starch, cross-linked polyvinyl Pyrrolidone, alginic acid or a salt thereof, such as sodium alginate. Follow up Additional excipients include, in particular, flow control agents and lubricants, such as silicic acid, talc, stearyl acid or its salts, such as magnesium stearate or calcium stearate and/or polyethylene glycol or its derivatives.

The coated tablet core is suitably provided by a suitable coating that is resistant to gastric juices. The substance used is, inter alia, a concentrated sugar solution, suitably a Labia gum, talc, polyvinylpyrrolidone, polyethylene glycol and / or containing titanium dioxide, a coating in a suitable organic solvent or solvent mixture. For the production of coatings resistant to gastric fluids or gastric fluids, suitable cellulose preparations are used. products such as acetylcellulose phthalate or hydroxypropylmethyl Cellulose phthalate. dyes or pigments, e.g. different active ingredient dosages mixed with tablets or coated tablet coatings for quantity identification or characterization be able to.

Pharmaceutical compositions that can be used orally include gelatin dry-filled capsules and Soft sealed caps of gelatin and a softening agent, such as glycerose or sorbitol It is a cell. The dry-filled capsules may contain fillers such as corn starch. binders and/or lubricants, such as talc or magnesium stearate. containing the active ingredient in the form of granules, preferably mixed with stabilizers. I can do it. Within soft capsules, the active ingredients are preferably in a suitable liquid vehicle. in a vehicle such as fatty oil, paraffin oil or liquid polyethylene glycol. Dissolved or suspended, it can also be added to stabilizers.

Furthermore, oral dosage forms can be manufactured in conventional manner, such as suspensions, e.g. form and in a concentration of about 5% to 20%, preferably about 10%, or For example, when 5 or 10+ ol is measured, the concentration to give a suitable single dose is It is a syrup containing the active ingredient. Further suitable forms are, for example, , also a fine powder or liquid concentrate for the manufacture of shakes in milk.

Pharmaceutical compositions that can be used rectally include, for example, a combination of a suppository base and an active ingredient. A suppository containing the combination. Suitable suppository bases include, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or high grade alcohol.

Compositions suitable for parenteral administration are particularly suitable in water-soluble form, e.g. Aqueous solutions of active ingredients or thickening substances, e.g. sodium carboxymethylcell. water containing loose, sorbitol and/or dextran, and optionally stabilizers. It is an injectable suspension. This active ingredient is also in the form of a lyophilizate, suitably with excipients. may be present therein and dissolved by addition of a suitable solvent prior to parenteral administration. can be understood.

For example, solutions such as those used for parenteral administration may also be used as infusion solutions. can be

The invention also relates to warm-blooded animals, i.e. mammals, and especially humans, preferably It also relates to methods of treating the above-mentioned pathological conditions in warm-blooded animals that require such treatment. Ru. When the compound of formula (1) of the present invention or a pharmaceutical salt thereof has a salt-forming group for prophylactic or therapeutic purposes and preferably Suitable for inhibiting carboxylase, especially ornithine decarboxylase against one of the above-mentioned diseases, such as tumors or protozoal infections, which responds to inhibition of used in the form of a pharmaceutical composition in an amount that is prophylactically or therapeutically active. . For a body weight of about 70 kg, about 0.3 g to about 15 g, preferably about 0.5 g. A daily dose of from 5 g to about 5 g of a compound according to the invention is now administered.

The pharmaceutical composition is preferably responsive to inhibition of ornithine decarboxylase. Administration to warm-blooded animals, e.g. humans, for the treatment or prevention of one of the above-mentioned diseases. Ornithine decarboxyl active against diseases that respond to inhibition of this enzyme (particularly in amounts that are active for inhibition of this enzyme) or a compound of formula (+) or a pharmaceutically acceptable salt thereof. It is.

The following examples serve to illustrate the invention without limiting its scope. stand.

The abbreviation BOC is the tert-butoxycarbonyl group, Il, p, point" and decow+p is "with 1 decomposition. Brine is chambered A saturated sodium chloride solution at room temperature. Temperatures are stated in degrees Celsius.

R7 value (transfer area covered by the compound to be measured vs. covered by the solvent front) The ratio of barred areas) is noted for thin layer chromatography. Solvents and diluents In the case of a mixture of yong! Write down the ratio.

8,77g (0,0381mol) of trans-(4-aminooxy)-N-B OC-cyclohexylamine and 180ml of 3.5M methanolic hydrochloric acid The mixture is stirred at room temperature for 3 hours and then evaporated in vacuo. residue Take up into methanol and evaporate the mixture again in vacuo. methanol Recrystallization of the residue from /diethyl ether gives the title compound, mp > 260 °C (changes to brown above 230 °C).

The starting compounds are synthesized as follows: a)) Lance-(4-aminooxy)-N-BOC-cyclohexylamine 16 , 2 g (0,004495 mo+) of 2-[trans-4-(N-BOC-ami -cyclohexyloxy]-1H-iso-indole-1,3(2H)-di A mixture of hydrazine hydrazine and 95 ml of hydrazine hydrate was stirred at room temperature for 172 hours. Stir and then add 145 ml of water and continue stirring for 172 hours. 450m After addition of 1 part of diethyl ether, the reaction mixture was stirred for an additional 2 hours and The ether phase is then separated. The aqueous phase was diluted with 200+ ol diethyl ether. Extract 3 times at a time. The combined ether phase was washed with brine and dried over sodium sulfate. and evaporate in vacuo to obtain the title compound in crystalline form, mp 10 5-106℃.

12ml (0,0718+nol) of diethyl azodi in 80ml benzene 14.62 g (0,06791 mol) of a solution of carboxylate (93%) of cis-4-(N-BOC-amine)-cyclo-hexanol, 11.1 g (0 ,068 mol) of N-hydroxyphthalimide, 17.84 g (0,068 mol) mol) of triphenylphosphine and 600 ml of benzene, 20 Add dropwise while stirring at -30°C.

The reaction mixture was further stirred at room temperature for 15 hours and then evaporated in vacuo. Ru. The residue was sieved using methylene chloride with particle size 0.04-0, 063+nm. Purify by flash chromatography on Rica gel. Product-containing picture After evaporation for minutes, the title compound is obtained as a crystalline residue, mp 207-208°C.

51.73 g (0,237+nol) in tetrahydrofuran of 100II11 A solution of di-tert-butyl dicarbonate of 100i+1 tetrahydro 52 g (0,2257 mol) of 4-amino-cyclohexanol in furan ( Fluka, Buchs.

5w1tzerland; cis/trans mixture; 50x in water) solution , and the mixture is stirred at room temperature for 15 hours. The reaction mixture is then evaporated in vacuo. Boil to dryness and stir the residue in 300 wells of diethyl ether. Filtration and After washing the crystals with diethyl ether and diethyl ether, the title compound in trans is obtained, melting point 1. 66℃ [Anti-Cancer Drug Design 2.25 (198 7)]. The filtrate was evaporated in vacuo and the residue was mixed with ethyl acetate/hexane. Flash chromatography on silica gel using (l; 2 and 1:1) Refined by fee. The title compound of cis is thus obtained, melting point 92-94°C. .

Similarly to Example 1, 0.875 g (0,0038 mol) of cis-(4-amino oxy)-N-BOC-cyclohexylamine and 10 ml of 3M methanolic salt Starting from hydrohydric acid but maintaining a reaction time of 20 hours, the title compound, melting point 1 Obtain 96-197°C (decomposed).

The starting compounds are synthesized as follows: a) cis-(4-aminooxy)-N-BOC-cyclohexylamine 2 g (0 ,00555+nol) to 2-[cis-4-(N-BOC-amino)-cyclo xyloxy]-It(-iso-indole-1,3(28)-dione and 12i +I hydrazine hydrate mixture was stirred at room temperature for 1 hour and 5(Ig Add ++I diethyl ether and continue stirring for 1.5 hours. next, The organic phase is separated and prepared analogously to Example 1a. The crystalline title compound obtained is It melted at 120-121°C.

b) 2-[cis-4-(N-BOC-amino)-cyclohexyloxy]-1H -isoindole-1,3(2H)-dione 4.1 ml (0,0244 mol) of diethyl azodicarboxylate (93 %) and 5 g (0,0232 mol) of trans-4-(N-BOC-amino) -Cyclohexanol (see Example 1c), 3.8 g (0,0232 mol) of N-hydroxyphthalimide, 6.1 g (0,0232 mol) of triphenate In a mixture of nylphosphine and 100+al of tetrahydrofuran, 20-30 Add dropwise at ℃. The reaction mixture was further stirred at room temperature for 15 hours, and Then evaporate in vacuo. Diethyl 1,2-hydrazine dicarboxylate and The oily residue was dissolved in ethyl acetate to separate the triphenylphosphine oxide. Dissolve, cool the solution to 0 °C and filter, evaporate the filtrate and add the same The operation is repeated one more time but using diethyl ether. diethyl ether The residue obtained after evaporation of ) by flash chromatography on silica gel . After evaporation of the product-containing fractions, the title compound is obtained as a crystalline residue, mp 134-1 35℃.

4.5 g (0,0261 mol) of trans-(3-aminooxy)-N-acetic acid tyl-cyclohexylamine and 22+nl of 2M sodium hydroxide solution (0,0 44i+ol) was heated under stirring for 15 hours. This reaction mixture Cool and thoroughly extract with methylene chloride and extract the organic phase with sodium sulfate. Dry on aluminum and evaporate in vacuo. Add a small amount of methane to this oily residue. Add a slight excess of 2M methanolic hydrochloric acid and mix. Evaporate something in a vacuum. Recrystallization of the residue from methanol/diethyl ether After reaction, the title compound is obtained, melting point 190° C. (decomposition).

The starting compounds are synthesized as follows: a) trans-(3-aminooxy)-N-acetyl-cyclohexylamine 1 3,4 g (0,0443 mol) of 2-[trans-3-(acetamino)-cy chlorohexyloxy]-1H-iso-indole-1,3(2H)-dione and 7 The mixture of o■I hydrazine hydrate is stirred at room temperature for 1 hour. 25 After addition of the diethyl ether on axis 1, stirring was continued for a further 2 hours at room temperature and then Next, the organic phase is separated and the hydrazine hydrate phase is evaporated in vacuo.

Add 500 nl of ethanol to the residue. Heat the mixture to reflux temperature and bring it to room temperature. Cool to 90°C, filter and evaporate the filtrate in vacuo. Treat the residue with chloride on silica gel using tyrene/methanol mixtures (50:1 and 9:1) Purify by flash chromatography. Evaporation of product-containing fractions and After recrystallization of the residue from methanol/diethyl ether, the title compound is obtained, Melting point 95-96°C.

b) 2-[) lance-3-(acetamino)-cyclohexyloxy]-1H- Isoindole-1,3(2H)-dione and 2-[cis-3-(acetamino )-cyclohexyloxy]-1H-isoindole-1,3(2H)-dione 46 ml (0,275+++ ol) of diethyl azodicarboxylate (9 3%), 39.3g (0,251nol) of 3-acetaminocyclohexano Rule [J, Am, Che+o.

Sac, 75.1345 (1953)], 40.78 g (0.25 mo l) of N-hydroxyphthalimide, 65.58 g (0.25 mo+) of tri- -20- in a mixture of ferlphosphine and 750+nl of tetrahydrofuran dropwise at 30° C. and then the reaction mixture was further stirred at room temperature for 15 hours. Stir. The precipitated product was filtered, washed with tetrahydrofuran and Recrystallize from ethanol. The title compound in trans is thus obtained, melting point 2 14-215℃.

To obtain the title compound in cis, the filtrate and mother liquor from the above recrystallization were combined and the evaporated in vacuo and the residue was dissolved in a toluene/isopropanol mixture (9 7,5:2.5 and 19:1) on silica gel. Purify by matography. After evaporation of the product-containing fractions, the title compound in cis Obtained as a crystalline residue, melting point 248-249°C.

Example 4: Cis-3-aminooxy-cyclohexylamine dihydroclide Similarly to Example 3, 1.38 g (0.08 mol) of cis-(3-aminooxy )-N-acetyl-cyclohexylamine and 7111 in 2M sodium hydroxide solution Starting from a solution (0,014nol), the title compound, melting point 193-194°C (min. solution).

The starting compounds are synthesized as follows: a) cis-(3-aminooxy IN-acetyl-cyclohexylamine 3,02 g(0,Olmol) of 2-[cis-3-(acetamino)-cyclohexyl- Pheasant]-1H-isoindole-1,3(2H)-dione (see Example 3b), 0.52 g + I of hydrazine hydrate and 60 ml of ethanol mixture Boil under reflux for 1 hour while stirring. Cool the mixture to room temperature and filter The filtrate was evaporated in vacuo and the residue was dissolved in a methylene chloride/methanol mixture. Flash chromatography on silica gel using compounds (50:1 and 50:3) Purify by matography. After evaporation of the product-containing fractions, the title compound was gradually added to Obtained as an oil that solidifies, melting point 94-96°C.

Example 5: Cis-3-aminooxymethyl-cyclohexylamine di2g (0 , O0555 mol) of 2-[cis-3-(N-BOC-amino)-cyclopene methylmethoxy]-l toisoindole-1,3(2H)-dione and 8mn1 The hydrazine hydrate mixture was stirred at room temperature for 1/2 hour, then 25 m 1 part of diethyl ether is added and stirring is continued for 1/2 hour. Separate the organic phase Separate and thoroughly extract the hydrazine hydrate with diethyl ether. Ru. The combined ether phase was washed with water and brine and dried over sodium sulfate. and evaporate in vacuo.

25 ml of 3M methanolic hydrochloric acid was added to the crude cis-3- Aminooxymethyl-N-BOC-cyclopentylamine, R, value: 0.15 ( silica gel/ethyl acetate:hexane (2+1)) and the reaction mixture Stir at room temperature for 15 hours. Evaporation in vacuum and ethanol/diethyl After recrystallization of the residue from ether, the title compound is obtained, melting point 137° C. (decomposition).

The starting compounds are synthesized as follows: 2.94+++1 (0,01755 mol) of diene in 10+nl of benzene A solution of thyl azodicarboxylate (93%) was added to 3.6 g (0,01672 +nol) cis-3-(N-BOC-amino)-cyclopentane methanol, 2.73 g (0.01673 mol) of N-hydroxyphthalimide, 4.4 9 g (0,01672 no triphenylphosphine and 60 ml benzene) dropwise into the mixture at 20-30°C.

After stirring the reaction mixture for 1 hour at room temperature, the precipitate formed during the reaction was filtered. , suspend the residue on the filter in benzene, and filter the suspension again. . Repeat the following procedure two or more times (residual Nidiethyl 1,2-hydra on the filter gin dicarboxylate) and the resulting filtrate, and vacuum evaporate inside.

Purification of the residue was carried out using ethyl acetate/hexane mixtures (1:3 and 1:1). Performed by flash chromatography on Rica gel.

The title compound is obtained, melting point 162-163°C.

b) 2.7 g of cis-3-(N-loOC-amino)-cyclopentane methanol ( 0,07141 nol) of sodium borohydride in 125 ml of methanol 3.8g (0,018w+ol) of N-BOC-2-Azabishiku o [2,2, 11 to a solution of butan 3-one in portions, stirred in a water bath within a 20 minute elapsed time. and add while cooling. The reaction mixture was kept at 0°C for 1 hour and then brought to room temperature. Stir further for 1 hour and add 4.08 ml (0,071 A solution of 4 mol) of acetic acid is then added dropwise and the mixture is evaporated to dryness in vacuo. . The crystalline residue is partitioned between methylene chloride and water. brine the organic phase After washing, drying over sodium sulfate and evaporation in vacuo, the title compound obtained as a crystalline residue, melting point 720,019 g (0,00075 moυ of 4- 50 ■ dimethylamino-pyridine! of 5.56 g in tetrahydrofuran ( 2-azabicyclo[2,2,1]butan-3-one [J , Org, Chetn, 39.564 (1974)] and 112g0.0 55nol) of di-tert-butyl dicarbonate and the mixture Stir at room temperature for 15 hours. Then evaporate it in vacuo and mash to remove the residue. Recrystallize from ethyl acetate/hexane. The title compound thus obtained is Melts at 89-90°C.

10.3 g (0.02973 mol) of 2-[cis-3-(N-BOC-amino )-cyclobutylmethoxy]-1H-isoindole-1,3(2H)-dione , 54+al of water and 451 of concentrated (approximately 12M) hydrochloric acid under reflux for 1.5 hours. Heat. The reaction mixture was then cooled to 0°C and filtered (with a lid). The residue on the fluoric acid) is washed with water, and the filtrate is evaporated in vacuo. Remove the residue Dissolve in ethanol and evaporate the solution again in vacuo.

After recrystallization of the residue from methanol/diethyl ether, the title compound is obtained, Melting point: 192°C (decomposed).

The starting compounds are synthesized as follows: a) 2-Ecis-3-(N-BOC-amino)-cyclobutylmethoxyco IH -isoindole-1,3(2H)-dione 6.54 ml (0,0391 mol) of diethyl acetate in 30 ml of benzene 7.5 g (0,03726 theories) of a solution of zodicarboxylate (93%) of cis-3-(N-BOC-amino)-cyclobutanemethanol, 6.08 g ( N-Hydroxyphthalimide, 9.774 g (0,03726 theories of) 03726a+ol) of triphenylphosphine and 120111 of benzene. Add dropwise to the mixture at 20-30°C.

The reaction mixture was stirred at room temperature for 2 hours and filtered to remove the crystalline residue (diethyl L , 2-hydrazine dicarboxylate) was washed with benzene and the filtrate was drained. Evaporate in vacuo. The residue was dissolved in ethyl acetate/hexane mixtures (l:3 and l:2 ) by flash chromatography on silica gel . After evaporation of the product-containing fractions and recrystallization of the residue from ethyl acetate/hexane, The title compound is obtained, melting point 131.5-132.5°C.

b) Cis-3-(N-BOC-amino)-cyclobutane methanol 98, 95m 1 (0,0989'5n+ol) of 1M tetrabutyl in tetrahydrofuran The ammonium fluoride solution was prepared in 75+nl of tetrahydrofuran. g(0,04947+nol) of cis-3-(N-BOC-amino)-1-(t hexyl-dimethylsilyl)oxymethyl-cyclobutane (-thexyl- = -2,3-dimethyl-2-butyl-) in a water bath with stirring and cooling. , drip.

The reaction mixture was further stirred at room temperature for 1.5 h and 1501 brine was then added. and the mixture is extracted five times with 100 nl of ethyl acetate each time. Combined After washing the combined organic phases with 100 ml of brine and evaporating in vacuo, the residue was , on silica gel using ethyl acetate/hexane mixtures (1:2 and 1:1). Purify by chromatography. The product-containing fractions were evaporated and the residue diluted. Recrystallize from sopropyl ether. The title compound is obtained, melting point 83-84°C. .

C) cis-3-(N-BOC-amino)-1-(thexyl-dimethylsilyl ) oxymethyl-cyclobutane and trans-(N-BOC-amino)-1-( thexyl-dimethylsilyl)oxymethyl-cyclobutane 49, 18+n1 (0,2495mol) of thexyldimethylchlorosilane was added to 400ml of 45.65 g (0,2268 mol) of 3-(N-BOC- amino)-cyclobutane methanol (EP 0366059 A2) and 40. 55! II (0,22681101) of 1,8-diazabicyclo[5,4,O ] Add dropwise to the solution of undec-7-ene while stirring. Add the reaction mixture Stir for 15 hours at room temperature and then evaporate in vacuo. Methyl chloride of the residue Partition between water and water, dry the organic phase over sodium sulfate, evaporate and evaporate. The oily residue was diluted with hexane and hexane/ethyl acetate mixtures (49:1 and 19:1). flash chromatography on silica gel using Purify by water. The product-containing fractions were evaporated to give the title compound in cis, R,=0 ．． 25 (silica gel/ethyl acetate:hexane (1:15)) and trans The title compound, R = 0.23, is obtained as an oil.

Similarly to Example 6, 7.25 g (0,0209311 ol) of 2-[trans- 3-(N-BOC-amino)-cyclobutylmethoxy]-1H-isoindole Starting from -1,3(2H)-dione, 35 nl water and 30 ml concentrated hydrochloric acid, The title compound is obtained, melting point 198°C (decomposition).

The starting compounds are synthesized as follows: a) 2-[trans-3-(N-BOC-amino)-cyclobutylmethoxy]- 1H-isoindole-1,3(2H)-dione Similar to Example 6a, 5.6 g (0,02782 theories of) trans-3-(N-BOC-amino)-cyclobu Tanmethanol, 4.54g (0,02783a+ol) of N-hydroxyphthalate of triphenylphosphine and and 5.12 m1 (0,0306 mo of diethyl azodicarboxylate ( Starting from 93%), the title compound is obtained, melting point 120-122°C.

b) trans-3-(N-BOC-amino)-cyclobutanemethanol Example 6 Similar to b, 13.2 g (0,03842 trans-3-(N-BOC-amino)-1-(thexyl-dime) silyl)oxymethyl-cyclobutane (see Example 6a) and tetra 76.8 ml (0.0768 mo I) of 1M tetrabutyl in hydrofuran Starting from ammonium fluoride solution, the title compound is obtained, mp 98-1 00℃.

The title compound 7b can also be synthesized as follows: 20+nl of benzene and 10 g of 3-(N-BOC-amino )-Cyclobutanemethanol [cis/trans mixture (EP　O366059A Trans-3-(N-BOC-amino) was added to the solution of [2] while stirring at room temperature. - Seed with few crystals of cyclobutanemethanol. Stir the mixture for 15 hours filter and wash the crystals with diisopropyl ether. pure mark The title compound is a crude product that still contains only about 3% of cis-3-(N-BOC-amino). ) - Diisopropyl ether Obtained by recrystallization from tel., melting point 98-99°C.

Example 8: 3-Aminooxymethyl-cyclobutylamine dihydro Example 6 and Similarly, 1.15 g (0,00332 theories of) of 2-[3-(N-BOC-amino) -cyclobutylmethoxy]-1) 1-isoindole-1,3(2H)-di Starting from 6+++I of water and 5 ml of concentrated hydrochloric acid, the title compound is obtained. Point 179°C (decomposition).

The starting compounds are synthesized as follows: Similar to Example 6a, 1.59 g (0,0079 mol) of 3-(N-BOC- amino)-cyclobutanemethanol (1!P 0366059 A2), 1. 29 g (0,0079101) of N-hydroxyphthalimide, 2.07 g ( 0,0079 mol) of triphenylphosphine and 1.39+ ol (0,0 Starting from 083 mol) of diethyl azodicarboxylate (93%), The title compound is obtained, melting point 108-109°C.

0,58g (0,001674mol) of 2-[3-(N-BOC-aminomethylene) )-cyclobutyloxy]-1H-isoindole-1,3(2H)-dione , 3 ml hydrazine hydrate and 10 ml diethyl ether at room temperature. Leave to stir for 1 to 2 hours. Separate the ether-containing phase and add 2+++1 water and Add 10 ml of diethyl ether to the hydrazine hydrate phase and Stir for 1/4 hour at room temperature and separate the organic phase. After the last operation, The combined ether phase was washed with water and brine, dried over sodium sulfate and and evaporate in vacuo. 10 μl of 3M methanolic hydrochloric acid were thus obtained. oily 3-aminooxy-N-BOC-cyclobutylmethylamine, R5 value =0.63 (silica gel/methylene chloride:methanol (9:1)), The reaction mixture is then stirred at room temperature for 15 hours. Evaporation and methanol in vacuum After recrystallization of the residue from L/diethyl ether, the title compound is obtained, mp 2 13°C (decomposition).

The starting compounds are synthesized as follows: a) 2-[3-(N-BOC-aminomethyl)-cyclobutyloxy]-l toy Twindol-1,3(2H)-dione As in Example 1b, except that ethyl acetate was used in flash chromatography. 15.24 g (0,07 57+no1) 3-(N-BOC-aminomethyl)-cyclobutanol, 12 ．． 35g (0,0757nol) of N-hydroxyphthalimide, 19.85 g (0,0757nol) of triphenylphosphine and 13.3+++1 ( Starting from diethyl azodicarboxylate C93% of The title compound melts at 161-162°C after recrystallization from ethyl acetate. Obtain a compound. By evaporation of the mother liquor and recrystallization of the residue from ethyl acetate/hexane A further batch of the title compound is obtained, mp 145-150<0>C.

b) 3-(N-BOC-aminomethyl)-cyclobutanol 100+nl Tet 59.2g (0,2712nol) of di-tert-butyl in lahydrofuran A solution of dicarbonate in 24.94 g of 18 h+l of tetrahydrofuran (0,246 axes of) suspension in 3-aminomethyl-cyclobutanol for 1 hour. Drop within the elapsed time. Add 80 ml of water to the reaction mixture and let stand at room temperature. Stirring is continued for a further 16 hours and the mixture is evaporated in vacuo. Obtained as crystal residue The title compound melts at 96-97°C.

c) 24.28 g (0.25 mo+) of 3-cyano-cyclobutanol [J, Aid, Chem, Soc.

93.110 (1971)], about 8% ethanolic ammonia solution of 5550 m Hydrogenate the liquid and 10.9 g of Raney nickel at 35°C. Hydrogen extraction After loading, the catalyst is filtered off and the filtrate is evaporated in vacuo. Obtained as crystal residue The title compound melts at 72°C.

Example 1O: Cis-2-aminooxymethyl-cyclopropylmethylamine. dihydrochloride 1.5g (0,00433mol) (7) 2-[SiX-2-(N-BOC-7mi) cyclopropylmethoxyto IH-isoindole-1,3(2H )-dione and 9 liters of hydrazine hydrate were stirred at room temperature for 172 hours. do. Then 9+nl of water was added to the reaction mixture and after a further 172 hours, Add 50 ml of methylene chloride. The reaction mixture was stirred for an additional 3 hours, then salt The methylene chloride phase was separated and the aqueous phase was washed each time with 30 parts of methylene chloride. Purify. The combined organic phases were washed with brine, dried over sodium sulfate and and evaporate. The oily cis-2-aminooxymethyl- N-BOC-cyclopropylmethylamine, R7 value = 0.13 (silica gel/ Ethyl acetate:hexane (1:1)) was dissolved in 18 ml of 3M methanolic hydrochloric acid. , and the reaction mixture is stirred at room temperature for 1 hour. Addition of diethyl ether After cooling in a water bath, the crystallized title compound was filtered off and dissolved in diethyl ether. Wash and dry, melting point 178-180°C (decomposition).

The starting compounds are synthesized as follows: 2.61 ml (0,0157 nol) of diethyl acetate in 15 ml of benzene 3g (0,0149nol) of zodicarboxylate (93%) (7) solution (7) Cis-2-(N-BOC-7minomethyl)-cyclopropane methanol , 2.43 g (0,014911 ol) of N-hydroxyphthalimide, 3. 9g (0,0149nol) of triphenylphosphine and 120+nl of ben Add dropwise to the mixture of zene at 20-30° C. with stirring. Bring the reaction mixture to the chamber Stir at room temperature for 16 hours and filter, washing the crystalline residue with benzene, The filtrate is evaporated in vacuo. The residue was dissolved in hexane and hexane/ethyl acetate. (2:1) by flash chromatography on silica gel using refine. Evaporation of product-containing fractions and recrystallization of the residue from methanol/hexane After reaction, the title compound is obtained, melting point 96-97°C.

b) cis-2-(N-BOC-aminomethyl)-cyclopropane methanol 10 24.45 g (0,1166 moles of dite) in 0 mL of tetrahydrofuran A solution of rt-butyl dicarbonate in 100n+I of tetrahydrofuran of 10.9 g (0,1078 IIlol) of cis-2-aminomethyl-cyclopropylene Lopanmethanol [J, Med, CheII+, Dan, 2304 (1988 )] and the mixture is stirred at room temperature for 15 hours. reaction mixture The material was evaporated in vacuo and the residue was purified using ethyl acetate/hexane (1:1). and purify by flash chromatography on silica gel. Contains product After evaporation of the fractions the title compound is obtained as a colorless oil, R7 value = 0.23 (silica gel/ethyl acetate:hexane (1:1)).

Similar to Example 1O, 0.46 g (0,00133 mol) of 2-[trans- 2-(N-BOC-aminomethyl)-cyclopropylmethoxy]-1H-isoy from ndole-1,3(2H)-dione and 3+nl hydrazine hydrate. Starting from the oily trans-2-aminooxymethyl-N-BOC-cyclopropylene Obtain pylmethylamine, R7 value = 0.07 (silica gel/ethyl acetate:hexyl Sun (1:1)).

This was dissolved in 4.5+nl of 3M methanolic hydrochloric acid and the reaction mixture was brought to room temperature. Stir at room temperature for 174 hours. From evaporation and ethanol/diethyl ether The title compound is obtained after crystallization of, melting point 175-176°C (decomposition).

The starting compounds are synthesized as follows: a) 2-[trans-2-(N-BOC-aminomethyl)-cyclopropylmeth xy]-IH-isoindole-1,3(2H)-dione Similar to Example 10a , 2.0 g (0,00994 Ilol) of trans-2-(N-BOC-amino methyl)-cyclopropane methanol, 1.62gC0,00994yaol) (DN-hydroxyphthalimide, 2.61g (0,00995mol) Triphenylphosphine and 1.75nl (0,01047+nol) of diene Starting from thyl azodicarboxylate (93°C%), the mixture was labeled as a colorless oil. The title compound is obtained, R2 value = 0.36 (silica gel/ethyl acetate:hexane (1 :l)).

b) trans-2-(N-BOC-aminomethyl)-cyclopropane methanol Similar to Example 10b, 11.69 g (0,1156 nol) of trans-2- Aminomethyl-cyclopropane methanol [J, Med, Chew+, Dan, 2304 (198B)] and] Starting from G. tert-Butylousi Carbone to obtain the title compound in oily form, R1 value = 0.16 (silica gel/ Ethyl acetate:hexane (1:1)).

19,65g (0,1141+nol) of trans-(4-aminooxy)-N -acetyl-cyclohexylamine and 140ml of 15g strong sodium hydroxide The mixture of solutions (0,525 axes) was heated to 100 °C under nitrogen atmosphere with stirring. and heat for 8 hours. After preparing analogously to Example 3, the title compound is obtained. Point〉260℃.

The starting compounds are synthesized as follows: a) trans-(4-aminooxy)-N-acetyl-cyclohexylamine 3 7.4 g (0,1237 mol) of 2-[trans-4-(acetamino)-cy Chlohexyloxy]-1H-isoindole-1,3(2H)-dione, 12 ．． 3I11 (0,248 ■of) of hydrazine humanate, 620ml of Tanol and 225 ml of methylene chloride are heated under reflux for 1 hour. Bring the mixture to room temperature and filter, washing the residue on the filter with methylene chloride, The filtrate is evaporated in vacuo. Take the crystal residue in 200ml of methylene chloride. The undissolved constituents are filtered off and the filtrate is again evaporated in vacuo. Last The operation is repeated once again using 250 w+I methylene chloride. title compound is thus obtained as a crystalline residue, melting point 105-106°C.

b) 2-[trans-4-(acetamino)-cyclohexyloxy]-1H- Isoindole-1,3(2H)-dione in 300 liters of tetrahydrofuran 39.5 ml (0,2413 mol) of diethyl azodicarboxylate ( 95%) (7) solution, 36.13 g (0,2298 mol) (7) -4-acetaminocyclohexanol [Ber, Dtsch, Chew, Ges, 72°995 (1939)], 37.49g (0,2298+no l) of N-hydroxyphthalimide, 60, 28 g of triphenylphosphine and 150h+1 of tetrahydrofuran with stirring at 20-30°C. while dripping. After stirring for 14 hours at room temperature, in each case the first Amounts of triphenylphosphine and diethyl azodicarboxylate used in was again added to the reaction mixture, stirring was continued for 6 hours, and the reaction mixture Leave the material at room temperature for 2.5 days. The crystal precipitate formed is filtered off and Wash with trahydrofuran. The title compound thus obtained was 210 Melts at -213°C. The yield can be further recrystallized or the mother liquor chromatographed. Rafi, - can be increased by.

Example 13: Capsule 0.25 g of a carton containing active ingredient, e.g. one of the compounds of Examples 1-12. Prepare capsules as follows: Composition (for 5000 capsules) Active ingredient 1250g Talc 180g Wheat starch 120g Magnesium stearate 80g Lactose 20g The fine powder material is passed through a 0.6+n+n width mesh sieve and mixed.

gelatin capsules in each case 0.33 g by capsule filling machine Fill portions of the mixture.

Example 14: Pharmacological data: The following results are used to determine the IC6° for inhibition of ODC from rat liver. From (above, 5eely and Pegg and Hayashi and Ka + ne j i), and T24 bladder (described above) Inhibition of tumor growth of bladder carcinoma cells was obtained by measuring the IC. Compound from example ODCT24 inhibition inhibition ICs. (μM) ICg. (μM) 1) 0.22 7.5 5) 0.083 ? ) 0.023 4.9 8) 0.02 4.15 9) 0.053 10) 0.47 Continuation of front page (81) Specified times EP (AT, BE, CH, DE.

DK, ES, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE) , 0A (BF, BJ, CF, CG, CI, CM, GA, GN, ML, MR, NE, SN.

TD, TG), AU, BB, BG, BR, BY, CA.

CN, CZ, FI, GE, HU, JP, KG, KP, KR, KZ, LK, LV, MD, MG, MN, MW, N.

, NZ, PL, RO, RU, SD, SI, SK, TJ.

TT, UA, US, UZ, VN

Claims (35)

[Claims] 1. Formula (I) below: H2N-(CH2)n-A-(CH2)m-O-NH2(I) {in the formula, A group is C3-C6 cycloalkylene; n is 0 or 1, and each other independently, m is 0 or 1; However, a) the distance between the aminooxy group H2N-O- and the amino group -NH2 is small. at most 3 and 4 carbon atoms, and b) two groups H2N-(CH2) n- and -(CH2)m-O-NH2 are not bonded to the same ring carbon atom of A. } and salts thereof. 2. During the ceremony, A group is C3-C6 cycloalkylene; n is 0 or 1, and each other independently, m is 0 or 1; However, a) the distance between the aminooxy group H2N-O- and the amino group -NH2 is small. at most 3 and 4 carbon atoms, and b) two groups H2N-(CH2) n- and -(CH2)m-O-NH2 are not bonded to the same ring carbon atom of A, A compound of formula (I) according to claim 1, or a salt thereof. 3. During the ceremony, the A group is C3-C6 cycloalkylene; n is 0; and m is 0 or 1; However, a) the distance between the aminooxy group H2N-O- and the amino group -NH2 is small. at most 3 and 4 carbon atoms, and b) two groups H2N-(CH2) n- and -(CH2)m-O-NH2 are not bonded to the same ring carbon atom of A, A compound of formula (I) according to claim 1, or a salt thereof. 4. During the ceremony, the A group is C3-C6 cycloalkylene; n is 0; and m is 0; However, a) the distance between the aminooxy group H2N-O- and the amino group -NH2 is small. at most 3 and 4 carbon atoms, and b) two groups H2N-(CH2) n- and -(CH2)m-O-NH2 are not bonded to the same ring carbon atom of A, A compound of formula (I) according to claim 1, or a salt thereof. 5. During the ceremony, A group is 1,2-cyclopropylene; 1,3-cyclobutylene; 1,3-cyclope or 1,3- or 1,4-cyclohexylene; m is 0 or 1, and n is 0 or 1 independently of m; However, if the distance between the aminooxy group H2N-O- and the amino group -NH2 is at least A compound of formula (I), wherein the compound also has no more than 3 and 4 carbon atoms; or a salt thereof. 6. During the ceremony, A group is 1,2-cyclopropylene; 1,3-cyclobutylene; 1,3-cyclope or 1,3- or 1,4-cyclohexylene; m is 0 or 1, and n is 0 or 1 independently of m; However, a) the distance between the aminooxy group H2N-O- and the amino group -NH2 is small. at least 3 and 4 carbon atoms, b) A is 1,2-cyclopropylene or In the case of 1,3-cyclobutylene, n is 0 or 1 and c) A is 1, Defined as anything other than 2-cyclopropylene or 1,3-cyclobutylene 2. A compound of formula (I) according to claim 1, in which case n is 0; or a salt thereof. 7. During the ceremony, A group is 1,2-cyclopropylene; 1,3-cyclobutylene; 1,3-cyclope or 1,3- or 1,4-cyclohexylene; n is 0; ri, and m is 0 or 1; However, if the distance between the aminooxy group H2N-O- and the amino group -NH2 is at least a compound of formula (I) according to claim 1, wherein also has up to 3 and 4 carbon atoms; or salt. 8. as claimed in any one of claims 1 to 7, present in cis or trans form. A compound of formula (I) or a salt thereof. 9. When an asymmetric carbon atom is present, cis or to as a pure enantiomer A compound of formula (I) according to any one of claims 1 to 7 in lance form, or is that salt. 10. During the ceremony, the A group is 1,4-cyclohexylene, n is 0, and m is 0, and the compound of formula (I) according to claim 1, present in cis or trans form. compound or its salt. 11. During the ceremony, the A group is 1,3-cyclobutylene, n is 0, and m is 0 or 1, and A compound of formula (I) according to claim 1, present in cis or trans form; Or its salt. 12. according to any of claims 10 or 11, present in trans form. A compound of formula (I) or a salt thereof. 13. During the ceremony, the A group is 1,2-cyclopropylene, n is 0 or 1, and m is 1, and A compound of formula (I) according to claim 1, present in cis or trans form; Or its salt. 14. A compound of formula (I) according to claim 13, existing in the cis form, or That salt. 15. trans-4-aminooxy-cyclohexy of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof. 16. cis-4-aminooxy-cyclohexyla of formula (I) according to claim 1; or a pharmaceutically acceptable salt thereof. 17. trans-3-aminooxy-cyclohexy of formula (I) according to claim 1; or a pharmaceutically acceptable salt thereof. 18. cis-3-aminooxy-cyclohexyla of formula (I) according to claim 1; or a pharmaceutically acceptable salt thereof. 19. cis-3-aminooxymethyl-cyclopene of formula (I) according to claim 1 Thylamine, or a pharmaceutically acceptable salt thereof. 20. cis-3-aminooxymethyl-cyclobutylene of formula (I) according to claim 1; or a pharmaceutically acceptable salt thereof. 21. trans-3-aminooxymethyl-cyclo of formula (I) according to claim 1; Butylamine, or a pharmaceutically acceptable salt thereof. 22. 3-aminooxymethyl-cyclobutyramide of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof. 23. 3-aminooxy-cyclobutylmethylamine of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof. 24. cis-2-aminooxymethyl-cyclopropylene of formula (I) according to claim 1; Pylmethylamine, or a pharmaceutically acceptable salt thereof. 25. trans-2-aminooxymethyl-cyclo of formula (I) according to claim 1; Propylmethylamine, or a pharmaceutically acceptable salt thereof. 26. A compound of formula (I) or a salt thereof according to any one of claims 1 to 25, or comprises a pharmaceutically acceptable carrier together with a pharmaceutically acceptable carrier. Pharmaceutical composition. 27. Diseases in warm-blooded animals that respond to inhibition of ornithine decarboxylase A pharmaceutical composition for the treatment or prevention of ornithine decarboxylase A compound of formula (I) according to claim 1 in an amount active against diseases responsive to inhibition of or a pharmaceutically acceptable salt thereof according to claim 1. A pharmaceutical composition comprising a carrier. 28. A method for treating diseases that respond to inhibition of ornithine decarboxylase. Prophylactically or therapeutically active ornithine dehydrogenase is administered to warm-blooded animals in need of such treatment. a carboxylase-inhibiting amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof; , a method comprising administering. 29. For the treatment of diseases that respond to inhibition of the enzyme ornithine decarboxylase or a pharmaceutically acceptable compound of formula (I) according to any one of claims 1 to 25 of The use of that salt. 30. Claim for the manufacture of a pharmaceutical composition for the treatment of tumors or protozoal infections 29. A compound of formula (I) or a salt thereof according to any one of 1 to 25. Use as described. 31. For the treatment of diseases that respond to inhibition of the enzyme ornithine decarboxylase Formula (I) according to any one of claims 1 to 25 for the preparation of a pharmaceutical composition of Use of compounds or salts thereof. 32. Any of claims 1 to 25 for the manufacture of a pharmaceutical composition for the treatment of tumors. 32. The use according to claim 31 of a compound of formula (I) or a salt thereof according to claim 1. 33. For use in methods for diagnostic or therapeutic treatment of the human or animal body. 26. A compound of formula (I) or a salt thereof according to any one of claims 1 to 25. 34. In the treatment of diseases that respond to inhibition of the enzyme ornithine decarboxylase A compound of formula (I) according to any one of claims 1 to 25 for use in That salt. 35. A method for producing a compound of formula (I) according to claim 1, comprising the following formula (II) ): X1X2N-(CH2)n-A-(CH2)m-O-NX2X4(II) {in the formula , A, n and m are as defined for compounds of formula (I), with the proviso that i ) The distance between the -O-NX3X4 group and the XlX2N- group is at least 3 and 4 or less and ii) two groups X1X2N-(CH2)n- and -(C H2) m-O-NX3X4 is not bonded to the same ring carbon atom of A, and X1, X2, X3 and X4 are each independently hydrogen or a monovalent amino protecting group; , X1 and X2, X3 and X4, or X1 and X2, and X3 and X4, respectively. can also be taken together to form a divalent protecting group, and other Functional groups are optionally present in protected form, with the proviso that X1, X2, X3 and X4 at least one of them is an amino protecting group. } or a salt thereof If a salt-forming group is present, cleave off the amino protecting group present and add the desired The obtained compound of formula (I) is converted into another compound of formula (I) by The mixture of isomers obtained is separated into individual isomers and/or the mixture of formula (I) obtained is divided into individual isomers. converting the free compound into a salt or converting the salt of the compound of formula (I) obtained into the free compound; A method comprising the step of converting the salt into a substance or another salt.